 |
|
|
| |
Single Agent Therapy with Lopinavir/Ritonavir Suppresses HIV-1 Viral Replication in ARV Naïve Patients: IMANI II - 96 Week Final Results
|
| |
| |
Reported by Jules Levin
ICAAC/IDSA Oct 28 2008 Wash DC
Gathe Jr. JC1 Yeh RF1,2, Mayberry C1, Nemecek J1, Miguel B1, Lipman BA3, Fath MJ3, Norton 1Therapeutic Concepts, P.A., Houston, TX, 2University of Houston, Houston, TX, 3Abbott, Abbott Park, IL
Single agent therapy (SAT) with lopinavir/ritonavir (LPV/r) has demonstrated successful control of viral replication as part of a variety of treatment strategies.1,2,3,4,5,6,7,8 However, there are limited data in LPV/r SAT in ARV naïve patients.9,10 Recent data demonstrated durable virologic control in ARV naïve patients at 96 weeks with this strategy.11,12
We present 96 week data of our IMANI II study of LPV/r SAT in ARV naïve subjects
Methods
IMANI II was a 48 week, phase II open label study examining, safety, virologic response and tolerability of LPV/r SAT in 39 ARV naïve patients. 48 week data showed 79% of subjects had VL<75 (ITT: M=F).10
We now present the final 96 week analysis from this study.
Eligible patients were all that completed the 48 week original study which was the entire group
Primary endpoints:
-- Proportion of subjects with plasma HIV-1 RNA (BDNA) <75 at week 96 (ITT M=F) calculated from baseline
Secondary endpoints
-- Virologic resistance in failing patients
-- CD4 count change
-- Change in lipid and triglyceride concentrations
Adherence was assessed by returned pill counts
All patients received LPV/r tablet formulation from weeks 48 to 96
Major Inclusion Criteria (day zero)
VL ≥ 2000 copies /ml
CD4+ < 400*
≥18 years of age·
PI -naïve 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 (day zero)
M184V mutation, or protease mutations at 32, 46, 47, 48, 50, 54, 73, 82, 84, or 90·
HBV co-infection, HCV requiring treatment
Hypersensitivity, pregnancy, contraindicated concomitant meds
Significant concomitant illness
Author Conclusions
IIn this study, the strategy of LPV/r SAT in ARV naïve patients, demonstrated durable virologic response · through week 96 with 74% achieving <75c/ml and 79% <400c/ml; ITT: M=F
IImmunologic improvement continued over the entire study with a CD4 median increase of 310 cells
WWhen rebound occurred it appeared to be associated with documented or suspected non-adherence.
In the first 48 weeks, 4 out of 6 rebounding patients re-suppressed upon adherence counseling and/or intensification. Low level viremia was seen in 5/39 (13%) following viral suppression without clinical or resistance sequele except in 1 subject who selected the I54V, but upon further investigation was not ARV naïve at baseline
IIn the second 48 weeks, only 3 subjects required resistance testing. In each case, only wild type virus was seen. Low level viremia was noted in 8 subjects and 6 of the 8 responded to adherence counseling. No clinical or resistance sequele were noted and no intensification was necessary.
LLPV/r tablets were generally well tolerated with no significant adverse events seen from weeks 48 to 96.·
Framingham risk scores did not change significantly from baseline with one subject began lipid lowering · agents during the entire study period
SSubjects who lost virologic response or had intermittent viremia did not develop protease inhibitor resis-tance.
These 96 week results, as well as CNS and female genital tract virologic control response data from IMANI II presented previously13,14, support the ongoing research into LPV/r as single agent therapy.
Author Discussion
TThe results from IMANI II provide complimentary data to the MONARK study which also showed 96 week virologic suppression and immunologic improvement with LPV/r SAT in ARV or PI naive pts. The re-sults from these SAT trials are not dissimilar to observed outcomes from 96 week triple BPI HAART tri-als.15,16,17
SSAT gives an opportunity to see the direct safety and tolerability of LPV/r tablets. AE's of any grade were rare and there were no significant changes in Framingham risk score over the 96 weeks.
Intermittent viremia was seen in a minority of subjects and were most often due to non-adherence. Dif-ferent from the MONARK trial, in IMANI II, we did not document the development of major PI resistance mutations. Of note, in MONARK, 5/83 subjects on LPV/r SAT developed protease associated resistance mutations but without phenotypic resistance to LPV/r or other PI's13. To minimize resistance, clinicians should be intolerant of significant periods of viremia independent of regimen choice. The resistance con-sequences of LPV/r SAT are comparable to published BPI HAART with preservation of phenotypic class sensitivity and without the in class and/or multiclass resistance of NNRTI HAART. 17,18,19,20,21
The success of IMANI II suggests LPV/r SAT may be an option for clinicians/patients. Specifically a de-sire to; avoid NRTI toxicity, reduce the cost of HAART, or simply patient preference are situations where this strategy could be applied.
Future Directions
IMANI III - fully enrolled - LPV/r SAT qd as a 48 week extension of IMANI II·
Single Genomic Sequencing·
- Will begin late 2008 to analyze whether baseline and/or developing minority variants play any role in predicting subjects with low level viremia.
EEconomics -planning stage- cost/efficacy analysis of LPV/r SAT in the IMANI II subjects
Still needed: Large multi-centered comparative trials to confirm findings these pilot results.
References
1Cameron W, et al. JID, 2008; 22:385-393.
2Nunes E.P., Oliveira M.S., Almeida M.M.T.B., Pilotto J.H., Ribeiro J.E., Faulhaber J.C. 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.
3Arribas 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.
4Arribas JR, et al. 11th EACS, Madrid 2007; #PS3/1.
5Pulido F, et al. AIDS 2008; 22:F1-F9.
6Nunes EP, et al. ibid, #P7.5/04
7Singh KP, e al. ibid, #P7.5/04
8Pierone G, Mieras J, et al. A pilot study of switch to lopinavir/ritonavir (LPV/r) monotherapy from non-nucleoside reverse transcriptase inhibitor-based therapy. HIV Clinical Trials 2006;7:237-45
9Gathe JC Jr, 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. Abstract MoOrB1057. Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand.
10Gathe JC Jr, Yeh RF, Mayberry C, et al. Single-agent therapy with lopinavir/ritonavir suppresses plasma HIV-1 viral replication in HIV-1 naive subjects: IMANI-2 48- week results. Program and abstracts of the 4th IAS Conference; July 22-25, 2007; Sydney, Australia. Abstract WEPEB034.
11Gathe, J et al. A 48 Week Pilot Study of the Safety and Efficacy of Lopinavir/Ritonavir (LPV/r) a Single Agent Therapy In ARV Naïve Patients Post Study Follow- up. The 8th International Congress On Drug Therapy in HIV Infection Glasgow, UK, November 12-16, 2006; 950521
12Delfraissy JF, Flandre P, Delaugerre C, et al, Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS. 2008;22:385-396.
13Ghosn, J et al. XVII IAC, Mexico, August 3-8, 2008; ABS TUPE 0113.
14Yeh 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.
15Yeh RF et al. Single Agent Therapy (SAT) with Lopinavir/ritonavir (LPV/r) Controls HIV-1 Viral Replication in the Female Genital Tract. 11th European AIDS
Conference (EACS) - Madrid, Spain - October 24-27, 2007; #7.70/2.
16Smith KY, et al. 17th IAC, Mexico 2008; #LBBPE1138
17Malan, N et al. 4th IAS Sydney 2007; WEPEB024.
18Riddler SA, et al. N Engl J Med 2008;358:2095-106.
19MacArthur, R et al. IAC 2006, ABS TU ABB0102
20Vonwyl, et al. 14th CROI 2007, Los Angeles; ABS 667.
21Phillips, A et al. 14th CROI 2007, Los Angeles; ABS 532.
|
| |
|
|
|
|
|
