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Simplified Antiretroviral Therapy in Special Populations: Clinical Outcomes at Week 48 of Lopinavir/ritonavir (LPV/r) Tablet Dosed Once Daily (QD) or Twice Daily (BID), Administered with ≥2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in Antiretroviral-experienced Subjects, Analyzed by Gender, Age, Race, Ethnicity, and Hepatitis Co-infection Status (Study M06-802)
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Reported by Jules Levin
EACS Nov 3 2009
Isabelle A. Gaultier, Linda M. Fredrick, Adebayo A. Lawal, William C. Woodward, Ashwaq E. Hermes,Karmin Y. Robinson-Morgan, Thomas J. Podsadecki, Barry M. Bernstein
Abbott, Abbott Park, IL USA
12th European AIDS Conference · 11-14 November 2009 · Cologne, Germany
Corresponding author: Isabelle A. Gaultier, Abbott, 200 Abbott Park Road, Dept. R48U, AP-30, Abbott Park, IL 60064-6146
Author Summary
Antiretroviral-experienced subjects grouped by gender, age, race, ethnicity, and hepatitis co-infection status did not have statistically significant differences in
efficacy when comparing LPV/r QD and BID dosing regimens, suggesting that LPV/r QD and BID dosing have comparable efficacy in diverse subpopulations
Safety and tolerability were also similar among subjects dosed with LPV/r QD and BID in the subgroups, with the few exceptions noted in the poster report. These findings are not considered clinically relevant and may reflect the relatively large number of comparisons performed.
Author Conclusion
Overall, these data indicate that LPV/r dosed QD and BID have similar efficacy and safety in a wide variety of subpopulations
Background
· Lopinavir inhibits the HIV-1 protease and is coformulated with a low dose of the pharmacokinetic enhancer ritonavir (LPV/r)
· LPV/r is indicated globally for treatment of HIV-1 infection when used in combination with other antiretroviral agents
· A previous study, M05-730, demonstrated noninferior efficacy with similar safety and tolerability of LPV/r 800/200 mg QD compared to 400/100 mg BID when dosed with 2 NRTIs in 664 treatment-naïve subjects followed for 96 weeks1
· Antiviral activity of LPV/r has also been demonstrated in protease inhibitor-experienced patients2, 3; however, LPV/r QD and BID dosing had not been directly compared in treatment-experienced patients prior to the M06-802 study
· Primary results of the M06-802 study indicated that through 48 weeks, LPV/r dosed QD or BID had similar efficacy, safety, and tolerability4
· As women, persons of age ≥45 years, non-white, Hispanic, and hepatitis co-infected patients comprise an increasing proportion of the HIV-1-infected population, the current analysis reports efficacy, safety, and tolerability data in these subgroups participating in the M06-802 study
Objective
The objective of this analysis is to compare the virologic response, change in CD4+ T-cell counts, adverse events (AEs), and laboratory abnormalities between the LPV/r QD and BID dosing arms in subpopulations of antiretroviral experienced subjects grouped by gender, age, race, ethnicity, and hepatitis co-infection status.
Results
All subjects had received prior antiretroviral therapy, but were naïve to LPV; there was no difference between LPV/r QD and BID arms in terms of use of prior therapy5
For the NRTI regimens used in the study, 41% were dosed QD, 12% were dosed BID, and 47% were dosed with a mixture of QD and BID agents. There was no statistically significant difference in the dosing frequency of NRTI regimens between the LPV/r QD and BID dosing groups.
Overall baseline demographic and HIV disease characteristics were similar between LPV/r QD and BID dosing groups, with the exception of a statistically significantly lower mean CD4+ T-cell count for the LPV/r QD dosing group at baseline
Baseline HIV-1 RNA Levels and CD4+ T-Cell Counts within Subgroups
Compared to the LPV/r QD group, the LPV/r BID group had a statistically significant higher baseline mean HIV-1 RNA level in the white and Hispanic subgroups, but a lower mean level in the non-white subgroup (Table 1)
Subjects in the LPV/r BID group had a statistically significantly higher baseline mean CD4+ T-cell count in the male, age <45 yrs, non-white, no Hispanic ethnicity reported, and Hepatitis B- and C- subgroups compared to those in the LPV/r QD group
Table 1. Baseline HIV-1 RNA Levels and CD4+ T-Cell Counts within Subgroups
Subject Disposition
A total of 135 (22.5%) subjects discontinued during the 48-week treatment period, with no statistically significant difference between LPV dosed QD (22.0%) and BID (23.1%)
The most common reasons provided by the investigator for discontinuation were lost to follow-up (6.7%), followed by adverse event and/or HIV-related event (6.0%), noncompliance (5.0%), and virological failure (3.7%), with no differences between LPV/r dosing groups
13 subjects in the LPV/r QD group and 21 in the LPV/r BID group discontinued due to an adverse event; additionally, 1 subject in each LPV/r dosing group discontinued due to an HIV-related event
-- Diarrhea was the most common adverse event leading to discontinuation, with no statistically significant difference between the LPV/r QD (7/300, 2.3%) and BID (6/299, 2.0%) dosing groups (P>0.999)
Within the subgroups, subjects aged ≥45 years receiving LPV/r BID were more likely than LPV/r QD subjects to discontinue due to any adverse/HIV-related event (4.3% QD, 12.9% BID, P=0.039), while Hepatitis B+ and/or C+ subjects receiving LPV/r BID were more likely tha LPV/r QD subjects to discontinue due to any adverse event (0% QD, 15.1% BID, P=0.001), particularly gastrointestinal disorders (0% QD, 11.3% BID, P=0.008)
Efficacy Evaluation
Using the FDA-TLOVR primary endpoint, 166/300 (55.3%) subjects in the LPV/r QD dosing group and 155/299 (51.8%) in the LPV/r BID dosing group were responders through 48 weeks, P=0.412 (Table 2 and Figure 1)
Using an OD analysis, 76.0% of QD LPV/r-dosed subjects and 72.2% of BID LPV/r-dosed subjects were responders (Figure 1)
The mean increase in CD4+ T-cell counts was similar between the QD and BID 121.5 cells/mm3 for BID, P=0.281) (Table 2 and Figure 2)
Within the subgroups at Week 48, there were no statistically significant differences between the LPV/r QD and BID dosing groups in either the proportion of subjects with plasma HIV-1 RNA levels <50 copies/mL or in CD4+ T-cell mean increases from baseline (Table 2)
Table 2. Proportion of Subjects With HIV-1 RNA <50 copies/mL at Week 48 and Mean Increases in CD4+ T-cell count from Baseline to 48 Weeks
Figure 1. Primary Effi cacy Endpoint at Week 48: Proportion of Subjects Responding (ITT FDA-TLOVR and OD Analyses)
Figure 2. CD4+ T-cell Count Mean Changes from Baseline (cells/mm3)
Safety
Table 3 shows drug-related adverse events of moderate-to-severe intensity occurring in ≥2.0% of subjects in either LPV/r dosing group
The only statistically significant difference between LPV/r dosing groups was for nausea (2.7% QD, 7.4% BID, P=0.009)
The most common drug-related, moderate-to-severe event was diarrhea, with no statistically significant difference between the LPV/r QD and BID dosing groups: 14.0% LPV/r QD, 11.0% LPV/r BID; P=0.323
The incidence of diarrhea that required treatment with other medication was similar between LPV/r dosing groups (16.0% QD, 16.4% BID; P=0.912)
In analysis of the adverse events listed in Table 3, subjects in the LPV/r BID group within the subgroups of age ≥45 yrs (1.1% QD, 8.6% BID, P=0.018), Hispanic (1.0% QD, 7.6% BID, P=0.036), and Hepatitis B- and C- (3.4% QD, 8.2% BID, P=0.031) reported a higher incidence of nausea than those in the LPV/r QD group. There were no other differences in rates of these adverse events within the subgroups.
Table 3. Subjects with Moderate-to-Severe Drug-Related Adverse Events Occurring in ≥2.0% of Either LPV/r Dosing Group
No clinically important differences between the LPV/r QD and BID dosing groups were observed for the potentially clinically significant laboratory values
Consistent with previous LPV/r studies, grade 3 or grade 4 lipid elevations were the most common potentially clinically significant laboratory abnormalities; the incidence was similar for cholesterol (6.5% QD, 7.5% BID) and triglycerides (4.8% QD, 6.4% BID) in both LPV/r dosing groups. These elevations occurred early in the study, rarely resulted in study drug discontinuation, and none were associated with pancreatitis.
Within the subgroup of Hepatitis B+ and C+ subjects, those in the LPV/r QD group were more likely to have lipase >2X ULN than those in the LPV/r BID group (9.8% QD, 0% BID, P=0.029). None of the elevations in lipase were associated with adverse events of pancreatitis.
No other clinically important differences between the LPV/r QD and BID dosing groups were observed on subgroup analysis of potentially clinically significant laboratory values
REFERENCES
1. Gonzalez-Garcia J, Cohen D, Johnson M, et al. Comparable Safety and Effi cacy With Once-daily (QD) Versus Twice-daily (BID) Dosing of Lopinavir/ritonavir (LPV/r) Tablets With Emtricitabine (FTC) + Tenofovir DF (TDF) in Antiretroviral (ARV)-naïve, HIV-1-infected Subjects: 96-Week Results of the Randomized Trial M05-730. Paper presented at: 5th IAS Conference on HIV Pathogenesis, Treatment, and Prevention 2009; Cape Town, South Africa.
2. Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodefi ciency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis. Mar 1 2002;185(5):599-607.
3. Kempf DJ, Isaacson JD, King MS, et al. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antivir Ther. Sep 2002;7(3):165-174.
4. Zajdenverg R, Badal-Faesen S, Andrade-Villanueva J, et al. on behalf of the M06-802 Study Team. Lopinavir/ritonavir (LPV/r) tablets administered once- (QD) or twice-daily (BID) with NRTIs in antiretroviral-experienced HIV-1 infected subjects: Results of a 48-week randomized trial (Study M06-802). Paper presented at: 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2009; Cape Town, South Africa.
5. King MS, Lawal A, Fredrick L, et al. Impact of baseline resistance on virologic
outcome with once-daily (QD) or twice-daily (BID) lopinavir/ritonavir (LPV/r) through 48 weeks of combination antiretroviral therapy in treatment-experienced, HIV-1- infected subjects. Paper presented at: 12th European AIDS Conference, 2009; Cologne, Germany.
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