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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
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Reported by Jules Levin
EACS Nov 3 2009 Cologne, Germany
Martin S. King, Adebayo A. Lawal, Linda M. Fredrick, Thomas J. Podsadecki, Barry M. Bernstein
Abbott, Abbott Park, IL USA
12th European AIDS Conference · 11-14 November 2009 · Cologne, Germany
Author Summary
Enrollment of Study M06-802 was designed to mirror clinical practice where physicians design an antiretroviral regimen based on treatment history, genotypic
resistance testing and interpretation, and local availability of antiretroviral agents
LPV/r dose frequency did not affect antiviral efficacy, regardless of the number of baseline mutations. This finding may reflect, in part, the high LPV trough concentrations achieved with both QD and BID dosing relative to viral IC50, even in subjects with up to 2-3 protease mutations.
Baseline 3TC/FTC resistance, as conferred by the presence of M184V/I, appeared to enhance virologic response rates. This effect is consistent with the
hypothesis that M184V imparts reduced viral fitness, rendering the virus hypersusceptible to other antiretroviral agents10; however, the effect of this mutation on treatment outcome requires further exploration.
The only statistically significant association between the number of baseline protease inhibitor-associated resistance mutations and virologic response was
seen with LPV-specific mutations in List 36
- Efficacy was similar within and across treatment groups in subjects with fewer than 3 baseline mutations from List 3; the number of subjects with 3 or
more mutations was insuffi cient to draw further conclusions
Author Conclusion
The impact of baseline protease resistance mutations is similar whether LPV/r is dosed QD or BID in treatment-experienced subjects
Background
· Lopinavir/ritonavir (LPV/r), a coformulated HIV-1 protease inhibitor (PI), has been used extensively in treating both antiretroviral-naïve and treatmentexperienced HIV-1-infected patients. Originally approved for twice-daily (BID) dosing of both treatment-naïve and experienced subjects, LPV/r has also been approved in the US, Europe and many other countries for once-daily (QD) dosing of treatment-naïve individuals.
· Prior studies in antiretroviral-naïve subjects indicated that QD dosing of LPV/r offered similar efficacy, safety, and tolerability as BID administration1, 2
· Study M06-802 was designed to test the antiviral activity, safety, and tolerability of LPV/r when dosed QD or BID in HIV-1-infected subjects with prior antiretroviral treatment3
· Individuals with antiretroviral experience may harbor HIV-1 virus with mutations in reverse transcriptase and protease
· Resistance-associated mutations have been shown to impact susceptibility to antiretroviral agents and treatment response4-6
Objective
To evaluate the influence of baseline resistance mutations on efficacy in antiretroviral-experienced subjects treated with LPV/r dosed QD and BID
METHODS
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/mL3
· If study participation was deemed appropriate by the investigator based on subject treatment history and results of genotypic resistance testing obtained
at the screening visit, subjects were randomized to receive LPV/r tablets either QD (800/200 mg) or BID (400/100 mg) with at least 2 investigator-selected,
locally available nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
Efficacy
· The primary efficacy endpoint was virologic response as analyzed using an intent-to-treat, time-to-loss of virologic response (ITT-TLOVR) algorithm
· Additionally, antiviral effi cacy was assessed using a dropouts-as-censored approach, which censored non-responders whose reason for failure was unlikely to be related to their virologic response (early discontinuations and subjects with a final HIV-1 RNA level <50 copies/mL)
· Logistic regression was used to evaluate the relationship between the number of baseline mutations and virologic response
Resistance
Protease resistance mutations were defined according to 4 lists
Lists 1 and 2 are derived from in vitro and clinical data for general protease inhibitor-associated resistance mutations4, 5, 7
- List 1: L10F/I/R/V, K20M/R, L24I, V32I, L33F, M36I, M46I/L, I47V/A, G48V, I50V, F53L, I54 (any change), A71V/T, G73S, V82A/F/T/S, I84V, L90M
- List 2: Any change at: D30, V32, M36, M46, I47, G48, I50, F53, I54, G73, V82, I84, N88, L90
List 3 reflects the US LPV/r prescribing information and clinical data on mutations specifi cally associated with resistance to LPV/r6, 8
- List 3: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, I84V
List 4 is based on the original lopinavir mutation score (LMS) and is provided in the EMEA Summary of Product Characteristics4, 9
- List 4: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, L90M
NRTI resistance-associated mutations were derived from the IAS-USA panel7
RESULTS
Subjects
Similar numbers of subjects were randomized and treated with LPV/r
QD (N=300) or BID (N=299); baseline demographics were comparable between
treatment groups, except that subjects in the BID-dosed group had a higher mean baseline CD4+ T-cell count (Table 1)
Subjects had similar patterns of prior antiretroviral treatment
- 94 subjects (16%) were NNRTI-naïve (Table 1)
- Overall, 189 subjects (32%) had a history of triple-class experience (prior use of NRTIs, NNRTIs, and PIs)
- Based on genotypic resistance screening at baseline, 29 subjects (5%) showed at least possible evidence of resistance to LPV
Background NRTI usage on study was comparable between treatment arms
- The number of active background NRTIs was similar between groups; the majority of subjects, 63% of QD- and BID-dosed subjects each, were susceptible to at least 2 NRTIs in the background regimen
- The most common background regimen consisting of 2 NRTIs was tenofovir DF (TDF) with either emtricitabine (FTC) or lamivudine (3TC), used by 89 QD subjects (30%) and 71 BID subjects (24%)
- The most common regimen consisting of 3 NRTIs, employed by 43 QD subjects (15%) and 51 BID subjects (17%), included TDF and zidovudine with either FTC or 3TC
Efficacy
The primary efficacy endpoint at 48 weeks revealed non-inferior antiviral activity of LPV/r dosed QD as compared to BID in treatment-experienced subjects
- By ITT-TLOVR analysis, 55.3% of QD and 51.8% of BID subjects had HIV-1 RNA <50 copies/mL3
- Other intent-to-treat and on-treatment analyses also demonstrated similar antiviral activity with LPV/r QD and BID3
Virologic response remained comparable between dosing groups when analyzed in subjects stratified by the number of active NRTIs at baseline (Table 2)
Table 2. Virologic Effi cacy (ITT-TLOVR) at Week 48 by Number of Active NRTIs at Baseline
Table 3. Antiviral Efficacy (ITT-TLOVR) at Week 48 Based on Number of Previous Protease Inhibitor Treatments
Relationship between Baseline Protease Inhibitor-associated Resistance Mutations and Virologic Response
The impact of the number of baseline mutations on response was comparable between QD and BID LPV/r dosing, and outcomes were similar when analyzed
by both ITT-TLOVR and dropouts-as-censored methods
- For List 1, a tendency for virologic response to be associated with the number of baseline mutations was observed (P=0.054); efficacy was similar in subjects with 4 or fewer List 1 mutations at baseline (Table 4)
Table 4. Virologic Response at Week 48 by Dropouts-as-censored Analysis in Subjects with List 1 Protease Inhibitor-associated Resistance Mutations at Baseline
aL10F/I/R/V, K20M/R, L24I, V32I, L33F, M36I, M46I/L, I47V/A, G48V, I50V, F53L, I54 (any change), A71V/T, G73S, V82A/F/T/S, I84V, L90M
bOR (95% CI): odds ratio (95% confi dence interval) per additional mutation
cP value comparing number of mutations with response, based on logistic regression chi-square test
The number of mutations from List 2 was not associated with virologic suppression (Table 5)
Table 5. Virologic Response at Week 48 by Dropouts-as-censored Analysis in Subjects with List 2 Protease Inhibitor-associated Resistance Mutations at Baseline
aAny change at: D30, V32, M36, M46, I47, G48, I50, F53, I54, G73, V82, I84, N88, L90
bOR (95% CI): odds ratio (95% confi dence interval) per additional mutation
cP value comparing number of mutations with response, based on logistic regression chi-square test
Virologic response was significantly associated with the number of baseline mutations according to List 3 (P=0.031); responses were similar for subjects
with 2 or fewer baseline List 3 mutations (Table 6)
Table 6. Virologic Response at Week 48 by Dropouts-as-censored Analysis in Subjects with List 3 Protease Inhibitor-associated Resistance Mutations at Baseline
There was no signifi cant effect of the number of baseline protease inhibitor-associated mutations from List 4 on virologic response (Table 7)
Table 7. Virologic Response at Week 48 by Dropouts-as-censored Analysis in Subjects with List 4 Protease Inhibitor-associated Resistance Mutations at Baseline
aL10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, L90M
bOR (95% CI): odds ratio (95% confi dence interval) per additional mutation
cP value comparing number of mutations with response, based on logistic regression chi-square test
Relationship between Baseline NRTI-associated Resistance and Virologic Response
Virologic response was higher among subjects with an M184V/I mutation in reverse transcriptase compared to those with wild-type virus at codon 184, although the response rate of the QD group appeared to be less affected by this mutation than the BID group (Table 8)
The effect of M184V/I on virologic response remained statistically significantly after adjustment for the number of protease inhibitor mutations, the number of active NRTIs, and adherence (data not shown)
Table 8. Virologic Response at Week 48 Based on Dropouts-as-censored Analysis, by Presence of M184V/I Mutation at Baseline
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2. 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.
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