icon- folder.gif   Conference Reports for NATAP  
 
  4th IAS (Intl AIDS Society) Conference on HIV Pathogenesis, Treatment and Prevention
Sydney, Australia
22-25 July 2007
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Single-agent Therapy with Lopinavir/ritonavir Suppresses Plasma HIV-1 Viral Replication in HIV-1 Naive Subjects: IMANI-2 48-Week Results
 
 
  Reported by Jules Levin
4th IAS Conference, Sydney, Australia, July 22-25, 2007
 
Gathe Jr. JC1, Yeh RF1,2, Mayberry C3, Nemecek J3, Miguel B1, Lipman BA4, Fath MJ4, Norton M4
1Therapeutic Concepts, Houston, TX; 2University of Houston, Houston, TX; 3Donald R. Watkins Foundation, Houston, TX; 4Abbott, Abbott Park, IL
 
A number of pilot trials utilizing lopinavir/ritonavir (LPV/r) as single-agent therapy have shown good viral suppression.1-3
 
Data employing the strategy of LPV/r as a single-agent ARV in naive subjects remain limited.4-7
 
Author Conclusions
LPV/r single-agent therapy demonstrated sustained virologic response through week 48 with 31/39 (79%) <75 c/mL and 33/39 (85%) <400 c/mL (ITT:M=F).
 
When rebound occurred it appeared to be associated with documented or suspected non-adherence.
 
4/6 rebounding subjects resuppressed upon adherence counseling and/or intensification.
 
In one subject, a single major PI mutation (IAS-USA mutation score) was selected (I54V). However, upon further investigation, this subject was not ARV naive.
 
5/39 (13%) of subjects who were responders demonstrated at least one episode of low-level viremia following initial viral suppression.
 
LPV/r as single therapy was generally well tolerated. The most prevalent adverse event was diarrhea, and was more likely to occur with the soft-gel capsule formulation.
 
Cholesterol and triglycerides increased from baseline, consistent with other LPV/r investigation. No subject required lipid lowering agents.
 
AUTHOR DISCUSSION
These results add to the growing body of knowledge on LPV/r single-agent therapy (SAT). While this study is non-comparative, it does provide additional evidence in several key areas:
--The virologic efficacy (79% <75 c/mL at week 48) and immunologic efficacy (CD4+ cell count increase from baseline = 234 cells/mm3) of single-agent LPV/r were comparable to that seen in triple agent HAART9 in treatment naive subjects.
--In this study, phenotypic resistance to protease inhibitor was not observed in naive subjects experiencing viremia suggesting minimal risk of resistance consequences.
--As seen with LPV/r triple therapy, most subjects experiencing viremia were able to resuppress with adherent counseling or nucleoside intensification.
 
The sustained efficacy seen in this study vs. recent studies with other boosted PIs given as SAT may be due to several unique factors:
--The coformulation of LPV/r vs. other boosted PIs may confer an efficacy advantage due to the inability to misdose RTV.
--Effective penetration of LPV into the CNS reservoir resulted in CSF LPV levels greater than the IC50 of WT virus and virologic control in the CSF.6
--The availability of LPV/r tablet during the study allowed subjects to switch from LPV/r SGC to tablet, providing additional benefits such as reduced PK variability and tolerability.7
--These benefits were not available in earlier studies of LPV/r single-agent therapy.10-12
 
These results support continued scientific study of LPV/r tablet as SAT and on-going work includes:
--Assessment of LPV penetration and virologic control in the female genital tract control during SAT
--Longer term follow-up to assess the durability of the LPV/r tablet SAT strategy
--Assessment of benefits and risks of simplification of stable subjects from BID to QD LPV/r single- agent therapy
--Pharmacoeconomic analyses
 
Methods
This is a Phase II, open-label, pilot study in 39 ARV-naive subjects examining the safety, viral response, and tolerability of Kaletra single-agent therapy administered 400/100 BID.
 
End-points:
Proportion of subjects with plasma HIV-1 RNA (branched DNA) <75 c/mL at week 48
 
Proportion of subjects with plasma HIV-1 RNA <400 c/mL at week 24 and 48
 
In addition, the IRB required that interim analysis at 24 weeks demonstrate viral suppression not more than 5% lower than LPV/r combination therapy as demonstrated in study M98-863.8
 
Adherence was assessed by returned pill counts.
 
Major Inclusion Criteria
--VL 32000 c/mL
--CD4+ <400*
-- >318 years of age
--PI-naive or has <7 days of prior ART with any licensed or investigational compound
--No active opportunistic infection
--CD4+ >400 allowed only with documented understanding of DHHS guidelines and desire for treatment.
 
Major Exclusion Criteria
--M184V mutation, or protease mutations at 32, 46, 47, 48, 50, 54, 73, 82, 84, or 90
--HBV coinfection, HCV requiring treatment
--Hypersensitivity, pregnancy, contraindicated concomitant meds
--Significant concomitant illness
 
Subject Disposition through Week 48
52 screened; 40 enrolled; 39 treated with LPV/r single-agent therapy; 3 (8%) intensified from 400/100 mg to 600/150 mg bid; 2 (5%) intensified with TDF/FTC; 34 continue on LPV/r alone.
 

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RESULTS
 
Baseline Characteristics

10 patients (26%) had >100,000 viral load; 10 had 51-200 CD4s, and 3 (8%) had <50 CD4s. 51% were Caucasian, 44% African-American.
 

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Adherence in Subjects with Virologic Failure
*Documented noncompliant during pharmacist's counseling due to a) avoiding her morning dose to minimize diarrhea if she was going to be out for sometime, b) alcohol intake caused her to forget taking her dose, c) falling asleep and forgetting her dose.
 Admitted poor compliance due to chronic diarrhea despite returning no medication.
Unannounced LPV/r trough 0.09 ug/mL at week 40.
 
The green lines in the graphs show percent of level of adherence
 

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Virologic Failures
 
Subject

011 Rebounded and resuppressed throughout study. Week 40 = VL 1,210 c/mL, week 44 VL = 793 c/mL and 139 c/mL at week 48. Dose intensified at week 48.
 
013 Dose intensified at week 40. Week 48 VL 139 c/mL. Subject withdrawn. Subject admitted he was not treatment naive at study start. He was untruthful in order to gain access to free medication. He had been on several regimens previously, including taking his partnerŐs Kaletra as single-agent "from time to time".
 
030 Poor compliance suspected. Adherence counseled. Rebounded throughout study. Intensified with TDF/FTC at week 40. Suppressed to VL <75 c/mL at week 44 and 48.
 
033 Poor compliance. Adherence counseled. Failure at week 16. Intensified with TDF/FTC. Suppressed below 400 c/mL by week 44 (VL 120 = c/mL), week 48 VL = 19,950 c/mL.
 
043 Poor compliance. Reached one-log VL decrease by week 4. Reached <400 c/mL by week 16. Rebounded at week 20. Adherence counseled. LPV/r dose intensified at week 28. Did not resuppress.
 
049 Periodic non-compliance suspected. Rebounded at week 32, resuppressed at week 44. VL 743 c/mL at week 48. Resuppressed again after week 48 with adherence counseling.
 
Cholesterol and Triglycerides Baseline through 48 Weeks
Median total cholesterol increased 29% from 163 at baseline to 213 at week 48; HDL 24% increase from 39 to 51; non-HDL-C increased 29% from 124 to 159; triglycerides increased 45% from 116 to 215.
 

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References
1 Cameron W, da Silva B, Arribas J, et al. A two-year randomized controlled clinical trial in antiretroviral-naive subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0201.
2 Nunes EP, Oliveira MS, Almeida MMTB., Pilotto JH, Ribeiro JE, Faulhaber JC, Norton M, Schechter M, Zajdenverg R. 48-week efficacy and safety results of simplification to single agent lopinavir/ritonavir (LPV/r) regimen in patients suppressed below 80 copies/mL on HAART - the KalMo study. Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUAB0103.
3 Arribas J, Pulido F, Delgado, R, et al. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: forty eight week results of a randomized, controlled, open label, clinical trial (OK04 Study). Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0203.
4 Gathe Jr. JC , Washington MY, Mayberry C, et al. IMANI-1 TC3WP Single drug HAART-proof of concept study. Pilot study of the safety and efficacy of Kaletra (LPV/r) as single drug HAART in HIV + ARV-naive patients: interim analysis of subjects completing final 48 week data. Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract MoOrB1057.
5 Delfraissy JF, Flandre P, Delaugerre C, et al. MONARK Trial (MONotherapy AntiRetroviral Kaletra): 48-week analysis of lopinavir/ritonavir (LPV/r) monotherapy compared to LPV/r + zidovudine/lamivudine (AZT/3TC) in antiretroviral-naive patients. Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0202.
6 Yeh RF, Letendre S, Novak I, et al. Single-agent therapy with lopinavir/ritonavir controls HIV-1 viral replication in the central nervous system. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California.
7 Gathe Jr. JC, Lipman B, Miguel B, et al. Tolerability and preference of lopinavir/ritonavir (Kaletra) capsules versus tablets as single agent therapy (IMANI-2). HIV8; 12-16 November 2006; Glasgow, Scotland. Abstract P62.
8 Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002; 346:2039-2046.
9 Bartlett J, Fath M, DeMasi R, et al. An updated systematic overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS. 2006; 20:2051-2064.
10 Delfraissy J-F, Flandre P, Delaugerre C, et al. MONARK Trial (MONontherapy AntiRetroviral Kaletra): 48-week analysis of lopinavir/ritonavir (LPV/r) monotherapy compared to LPV/r + zidovudine/lamivudine (AZT/3TC) in antiretroviral-naive patients. XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0202.
11 Arribas J, Pulido F, Delgado, R, et al. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: forty eight week results of a randomized, controlled, open label, clinical trial (OK04 Study). XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0203.
12 Cameron W, da Silva B, Arribas J, et al. A two-year randomized controlled clinical trial in antiretroviral-naive subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada, 2006. Abstract THLB0201.