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Single-drug HAART (Lopinavir/r) for maintenance of HIV viral suppression
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--Week 24 results of a randomized, open-label, pilot clinical trial
--Only Kaletra Study (OK)
Jose Arribas and colleagues (Madrid, Spain) reported this study at the VX Intl AIDS Conference. Poster B4486.
AUTHORS CONCLUDED
--In contrast to previous trials of induction-maintenance strategies, a large proportion of patients (81%) simplified to lopinavir/ritonavir single-drug HAART remain virologically supressed after 24 weeks of follow up.
--Preliminary data show that failure of lopinavir/ritonavir single-drug HAART is not associated with the development of resistance mutations.
--Patients with maintenance failure on lopinavir/ritonavir single-drug HAART in our study could be safely reinduced with previous NRTIs.
--The OK Trial continues. Full 48 weeks results will be available by the end of July-04.
LIPIDS
--In the OK study, withdrawal of nucleosides in patients treated with lopinavir/ritonavir-based HAART did not have an significant impact on serum lipid profiles after 24 weeks of follow-up.
--authors commented: The ability of our study to find significant changes in lipid values after stopping nucleosides was limited by several factors:
Small sample size (pilot study). At baseline, median lipid values in the group which stopped NRTIs were within the normal range. Of the 19 patients who stopped NRTIs, only 8 were receiving d4T. Longer follow-up needed.
BASELINE LIPIDS
CHOL: 176-183
LDL-CHOL: 84-104
HDL-CHOL: 44-43
TG: 186-208
BACKGROUND FROM AUTHORS
The concept of induction and maintenance therapy is attractive:
--Less exposure to potentially harmful drugs.
--Preserving future treatment options.
--Minimising risk of side-effects or resistance.
--Fewer tablets to take, helping with compliance.
--Less expensive.
Three previous trials (ACTG 343, Trilege, ADAMS) performed:
--Single or dual drug regimens associated with a very high risk of virological failure. Trials prematurely terminated.
Lopinavir/r is an appropriate candidate for single drug HAART:
--High potency.
--High genetic and pharmacological barriers to resistance.
--Extremely low risk of resistance in antiretroviral-naïve patients.
--Non-controlled experiences suggest a possible use of lopinavir/r as single-drug HAART (Pierone, Gathe).
STUDY OBJECTIVES
Primary
To determine the feasability of maintaining virological control with lopinavir/ritonavir monotherapy in patients who have had undetectable viral load for 6 months on lopinavir/ritonavir + 2 NRTIs. This is a 96-week study.
Secondary
--Proportion of subjects with plasma HIV <400 copies/mL at 6 and 12 months.
--Proportion of subjects with plasma HIV <50 copies/mL at 6 and 12 months.
--Incidence of resistance to lopinavir/ritonavir.
--Impact on lipid values (poster WePeB5925).
--To determine sample size estimations for a subsequent comparative trial with appropriate power.
PATIENTS & METHODS
Design
--Investigator-initiated, randomized, open-label, multicenter, pilot study.
--42 patients receiving lopinavir/r + 2 NRTIs (or 1 NRTI + TDF) were randomized 1:1 to continue or to stop the NRTIs (or 1 NRTI + TDF).
Main Inclusion Criteria
--Continuous antiretroviral treatment during at least the prior 6 months. Receiving Lopinavir/r + 2 NRTIs (or 1 NRTI + TDF) >=4 weeks.
--No history of virological failure while receiving a PI.
--Change of PIs for adverse events or other reasons allowed if changes had been made while viral load was <50 copies/mL.
--viral load <50 copies/mL for at least 6 months prior to study entry.
DEFINITION OF MAINTENANCE FAILURE PER PROTOCOL ANALYSIS (ITT-MD=F)
--2 viral loads >500 c/mL 2 weeks apart or
--Change of randomized therapy or
--Treatment discontinuation or
--Lost to follow up
BASELINE CHARACTERISTICS
There were no statistical differences between the two study arms.
| OK Kaletra Mono | Triple | | N | 21 | 21 | | Age | 42 | 42 | | Male | 81% | 86% | | RISK FACTOR IVDU | 38% | 29% | | MSM | 24% | 38% | | Hetero | 43% | 33% | | CDC CIII | 52% | 33% | | AIDS | 57% | 29% | | MEDIAN-HIV-RNA | 5.11 log | 4.93 log | | months <50 c/ml | 28.6 | 15.7 | | CD4 Baseline | 662 | 585 | | Nadir | 139 | 90 | | HCV coinfect | 48% | 48% |
BASELINE PRIOR HAART
| OK | Triple | | Mos on LPV/r | 13 | 13 | | LPV/r 1st PI | 29% | 29% | | LPV/r 2nd PI | 62% | 48% | | LPV/r 3rd PI | 9.5% | 24% |
Other PIs Prior to LPV/r
| NFV | 14%^ | 29% | | IDV | 19% | 43% | | RTV | 29% | 14% | | SQV | 9.5% | |
NRTIs pre-randomization
| AZT-3TC | 33% | 43% | | D4T-3TC | 38% | 29% | | Others | 29% | 29% |
PATIENT DISPOSITION
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OK
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Triple
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N
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21
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21
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Lost to followup
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1
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0
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Maintenance failure
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3
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0
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Per protocol Disct for AE
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0
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0
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Still on study
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20
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21
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HIV RNA <50 copies/ml (ITT, MD=F) at WEEK 24
100% on triple (n=21)
81% on OK (n=21): 1 lost to followup; 3 maintenance failures
VIRAL BLIPS
Blip = HIV RNA >50 c/ml with subsequent sample <50
Maintenance failure per protocol=2 viral loads >500 c/ml 2 weeks apart or change of randomized therapy or treatment discontinuation or lost to followup.
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Week
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OK
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Triple
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1
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0
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0
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2
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1 (202 c/ml)
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0
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4
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0
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0
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8
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1 (61 c/ml)
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0
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12
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0
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0
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16
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0
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0
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24
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1 (94 c/ml)
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0
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CD4 CHANGE FROM BASELINE
On the OK Kaletra monotherapy regimen mean CD4 count was 50 cells higher at week 24 compared to baseline vs 7 cells higher in the triple HAART regimen.
HEMATOCRIT
On the Kaletra monotherapy arm, mean hematocrit increased from 43.9 at baseline to 47.8 at week 24 (p=0.031). While on the triple regimen mean hematocrit was 44.6 at baseline & 45.3 at week 24 (p=ns).
MAINTENANCE FAILURES
Patient 17.
--adherence 59% during first 12 weeks. Measured by prescription refill. Patient was quite adherent before starting the study. She started to use illicit drugs shortly after starting study.
--LPV trough: 6 ug/mL at baseline
--viral load was undetectable & increased at week 8 to about 4,000 c/ml
--at week 12 genotype L63P & LPV trough was 1.11 ug/mL
--at week 16, genotype L63P and VL was 20,000 c/ml, and lost to follow-up
Patient 10.
--LPV trough 3.81 ug/mL at baseline
--week 12, LPV trough 4.40 ug/mL, viral load rebounded from undetectable to 500; no genotypic mutations
--week 24, VL 500 c/ml, no genotypic mutations, and reintroduced AZT/3TC
--VL went back down to undetectable
Patient 14.
--LPV trough 5.78 ug/mL at baseline
--at week 16, VL started to increase but still <500; LPV trough 4.57
--at week 24, VL about 1000 c/ml; genotype V77I
--patient could not be reached between week 24 & 32 and kept taking LPV/r single drug during that period
--week 32, VL 1000 c/ml, genotype V77I; reintroduced AZT/3TC
--week 36, VL undetectable
--week 48, VL undetectable
Patient 12.
--LPV trough 9.4 ug/mL at baseline
--at week 24, VL started to increase but still <500 c/ml; LPV trough 5.7 ug/mL
--week 30, VL 1000 c/ml; genotype L63P, V77I
--week 32, VL 1,500 c/ml & reintroduced d4T/3TC
--week 36, VL undetectable
--week 48, VL undetectable
MAINTENANCE OUTCOME (ONLY KALETRA ARM) ACCORDING TO TIME WITH VIROLOGIC SUPPRESSION PRIOR TO RANDOMIZATION
The three maintenance failures all were <50 c/ml HIV RNA for 24 weeks prior to receiving LPV/r alone.
All of the other patients were <50 c/ml for longer than 24 weeks and many of the patients were <50 c/ml 1-4 years prior to simplification.
COMPARISON OF TREATMENT FACTORS IN PATIENTS TREATED WITH ONLY KALETRA WITH & WITHOUT PROTOCOL DEFINED MAINTENANCE FAILURE
The mean days HIV RNA <50 copies/ml prior to LPV/r alone: 1,095 (range 277-2,316) for patients in this study <50 c/ml at week 24 vs 218 days (range 208-229) for patients who were maintenance failures (p=0.002).
OTHER FACTORS EXAMINED
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HIV-RNA<50
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Maintenance
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At wk 24
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failures
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P
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N
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17
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3
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AIDS
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58%
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67%
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ns
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HIV RNA pre-HAART
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218,000
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57,000
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ns
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CD4 cells (mean) Baseline
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658
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437
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ns
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Nadir
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158
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43
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ns
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4 wks increase
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9
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127
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ns
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TOTAL MONTHS on LPV/r PRIOR LPV/r alone (mean)
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17
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17
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ns
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LPV/r 1st PI
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23%
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67%
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ns
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Pt 17, poor adherence, ecluded from analysis.
Comments. three patients failed Lopinavir/r single-drug HAART despite adequate lopinavir trough levels and without the development of primary PI mutations. Why?
Non-detected low level viral replication at baseline?
--Shorter induction times in failures suggest possible residual replication at baseline.
--Ultrasensitive PCR (LOQ = 3 copies/mL) in progress.
Minority populations of HIV-resistant virus?
--Single genome sequencing in progress, but rebound in viral load would likely have been accompanied by resistant virus as the majority species if resistance were the primary cause of failure.
--Active follow-up of patients after reinduction in progress.
Host issues?
--Anatomically protected site in which PIs do not penetrate.
--Overexpression of cellular efflux pumps.
Other?
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