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  EACS - 12th European AIDS Conference
November 11-14, 2009
Cologne, Germany
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Improved Treatment Compliance with Once-Daily (QD) Compared to Twice-Daily (BID) Lopinavir/ritonavir (LPV/r) in HIV-1-Infected, Antiretroviral-Experienced Subjects
  Reported by Jules Levin
12th European AIDS Conference · 11-14 November 2009 · Cologne, Germany
Martin S. King, Adebayo A. Lawal, Linda M. Fredrick, Richard A. Rode, Thomas J. Podsadecki, Barry M. Bernstein
Abbott, Abbott Park, IL USA
Author Summary
Consistent with prior studies on predictors of antiretroviral adherence6, mean adherence rates were lower across both LPV/r QD and BID dosing groups in this treatment-experienced population compared to rates previously observed with LPV/r in naïve subjects1
- Treatment-experienced subjects may include individuals with poor adherence to prior antiretroviral regimens, which has been described to predict adherence to the current regimen6
LPV/r dose frequency did not affect virologic outcome despite increased adherence with QD LPV/r administration
The results suggest that, among subjects achieving virologic suppression, the maintenance of virologic response was less sensitive to reduced adherence with QD-dosed LPV/r than with BID-dosed LPV/r
- Adherence was not predictive of virologic rebound in subjects achieving virologic response when LPV/r was administered QD; however, the lowest levels of adherence were associated with loss of virologic response in subjects receiving LPV/r BID who initially achieved virologic suppression
- Further research is necessary to fully understand the relationship between virologic efficacy and adherence, particularly its impact on the maintenance of virologic response in antiretroviral-experienced subjects treated with LPV/r QD and BID
As observed in antiretroviral-naïve subjects, QD administration of LPV/r features increased adherence compared to BID LPV/r dosing in treatment-experienced, HIV-1-infected subjects
· Lopinavir/ritonavir (LPV/r), a coformulated HIV-1 protease inhibitor (PI), has been approved for use in combination therapy in both antiretroviral-naïve and treatment-experienced HIV-1-infected patients
· Prior studies of antiretroviral-naïve subjects indicated that once-daily (QD) dosing of LPV/r offered similar safety and antiviral activity as twice-daily (BID) administration1-3, leading to approval for QD administration in antiretroviral-naïve individuals in the US and EU
· Prior analyses also noted that QD dosing resulted in greater treatment compliance than BID administration1, 4
· Study M06-802 was designed to test the safety, tolerability, and efficacy of QD compared to BID LPV/r in HIV-1-infected subjects with prior antiretroviral treatment experience, but who were naïve to LPV/r5
· QD and BID LPV/r demonstrated therapeutic equivalence through 48 weeks of treatment in antiretroviral-experienced subjects in Study M06-8025
To examine the relationship between LPV/r adherence and virologic response in antiretroviral-experienced subjects
Study Design

Study M06-802 was a Phase 3, randomized, open label trial that included antiretroviral-experienced subjects failing their current regimen with plasma HIV-1 RNA >1000 copies/mL5
Subjects received LPV/r tablets QD (800/200 mg, N=300) or BID (400/100 mg, N=299) with at least 2 investigator-selected nuceloside/nucleotide reverse transcriptase inhibitors (NRTIs)




Adherence data through 8 weeks were available for 256 subjects in the LPV/r QD dosing group and 265 subjects in the LPV/r BID dosing group. There was no between-group difference in the proportion of subjects with unavailable adherence data. The most frequently reported reason for the absence of adherence data was the loss of the MEMS® monitor.
For subjects with available adherence data, baseline characteristics were similar between LPV/r treatment groups (Table 1)
Table 1. Baseline Demographics of Subjects with Available Adherence Data


The dose frequency of background NRTIs was comparable between treatment groups (Table 2)
Table 2. Subjects with Indicated Dose Frequency of NRTI Regimen


Across all measures of treatment compliance, LPV/r QD-dosed subjects had significantly greater mean adherence compared to LPV/r BID-dosed subjects (Table 3)
Table 3. Mean Adherence Rates


Adherence measures were highly correlated with one another (R≥0.80, P<0.001 for TAC vs. COD, TAC vs. TIC, and COD vs. TIC from baseline to Week 8)
Adherence and Virologic Response All adherence measures were strongly correlated with virologic response - When treatment groups were combined for analysis, adherence was strongly and broadly associated with achieving and maintaining virologic response through 48 weeks (Figure 1A)
-- Among all subjects who achieved initial viral suppression (HIV-1 RNA <50 copies/mL), only the lowest quartile of adherence was associated with an increased risk of virologic rebound through 48 weeks (Figure 1B)
Figure 1. Relationship Between Timing Compliance From Baseline to Week 8 and Virologic Response Through 48 Weeks (All Subjects)



However, differences in the relationship between adherence and virologic response were noted when the treatment groups were analyzed individually
- In the QD LPV/r group, while adherence was associated with the achievement of initial viral suppression (Figure 2A), it was not significantly associated with virologic rebound among subjects achieving initial suppression (Figure 2B)
The lowest adherence quartile had a risk of virologic rebound similar to that of the highest adherence quartile
- In the BID LPV/r group, adherence was again associated with the achievement of initial viral suppression (Figure 3A), but in contrast to the QD-dosed LPV/r group, adherence remained significantly associated with the risk of virologic rebound among those with initial viral suppression (Figure 3B)
The two lowest adherence quartiles had a higher risk of virologic rebound than the two highest adherence quartiles
Sensitivity analyses using other adherence measures (TAC or COD) or measuring adherence through other timepoints (Baseline to Week 4 or Baseline to Week 24) were consistent with these results (data not shown)
Figure 2. Relationship Between Timing Compliance From Baseline to Week 8 and Virologic Response Through 48 Weeks (QD Subjects)



Figure 3. Relationship Between Timing Compliance From Baseline to Week 8 and Virologic Response Through 48 Weeks (BID Subjects)


LPV/r dosing frequency (QD versus BID) did not affect virologic response, before or after adjustment for adherence (Table 4)
Dosing frequency of the NRTI regimen was not associated with loss of virologic response, and the effect of treatment group remained nonsignificant after adjustment for NRTI dosing frequency (data not shown)


Table 4. Effect of LPV/r Dose Frequency on Virologic Response


*HR: Hazard Ratio; 95% CI: 95% confi dence interval; values >1.0 favor longer duration of response in the QD group.
1. Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses. 2007;23:1505-1514.
2. Eron JJ, Feinberg J, Kessler HA, et al. Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial. J Infect Dis. 15 2004;189:265-272.
3. Gathe J, da Silva BA, Cohen DE, et al. A Once-Daily Lopinavir/Ritonavir- Based Regimen Is Noninferior to Twice-Daily Dosing and Results in Similar Safety and Tolerability in Antiretroviral-Naive Subjects Through 48 Weeks. J Acquir Immune Defi c Syndr. 2009;50:474-481.
4. Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better Adherence with Once-Daily Antiretroviral Regimens: A Meta-Analysis. Clin Infect Dis. 2009;48:484-488.
5. Zajdenverg R, Badal-Faesen S, Andrade-Villanueva J, et al. Lopinavir/ (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; 19-22 July, 2009; Cape Town, South Africa.
6. Mathews WC, Mar-Tang M, Ballard C, et al. Prevalence, predictors, and outcomes of early adherence after starting or changing antiretroviral therapy. AIDS Patient Care STDs. 2002;16:157-172.