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Kaletra 4 Yr Followup in Treatment-Experienced; New Formulation of Kaletra
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"Long-term antiretroviral efficacy and safety of lopinavir/ritonavir in HAART-experienced subjects: 4 year follow-up study"
AIDS: Volume 19(16) 4 November 2005 p 1934-1936
Bongiovanni, Marcoa; Bini, Teresaa; Capetti, Amedeob; Trovati, Serenaa; Di Biagio, Antonioc; Tordato, Federicaa; Monforte, Antonella d'Arminioa
aInstitute of Infectious Diseases and Tropical Medicine, University of Milan, Milan, Italy
bSecond Division of Infectious Diseases, L. Sacco Hospital, Milan, Italy
cInstitute of Infectious Diseases, University of Genova, Genoa, Italy.
".....By ITT analysis, after 4 years of follow-up 64.8% of patients achieved an HIV-RNA level of less than 50 copies/ml, with corresponding on-treatment results of 83.5%....."
Within a few weeks the FDA is expected to announce approval of the new Meltrex formulation of Kaletra (lopinavir/ritonavir). The new formulation is in tablet form & will be a reduced pill count, allow for room temperature storage of Kaletra (no refrigeration necessary), and there are no food requirements so you can eat or not eat when taking Kaletra's new formulation. The new formulation is expected to have fewer side effects associated with it such as diarrhea which has been associated with Kaletra. Use of the new formulation should improve overall response rates. A presentation on the new formulation was made at the International AIDS Conference in Rio this past Summer of 2005, where pharmacokinetics (PK) study data was presented showing lower variability of lopinavir levels compared to the currently used Kaletra soft-gel capsules, this should help in improve\ing response rates to Kaletra. The full report is available at this link:
New Kaletra Tablet PK Study
http://www.natap.org/2005/ias/ias_5.htm
The introduction of HAART into clinical practice has resulted in a marked improvement in the survival of patients infected with HIV, as a consequence of the suppression of HIV replication and the consequent recovery of the immune system [1,2].
Lopinavir, co-formulated with a low dose of ritonavir (LPV/r) to enhance its pharmacokinetic profile [3], is at the moment considered to be one of the most potent antiretroviral drugs and is used in both naive and multi-experienced patients [4-6].
Few reports have assessed the long-term antiretroviral efficacy and tolerability of LPV/r in naive patients [7], and no data are at the moment available in experienced patients. This report describes the immunovirological outcome and the safety of the use of LPV/r in HIV-infected, HAART-experienced patients during a 4-year long follow-up.
This observational study included all patients starting LPV/r-containing HAART (at a dose of 400/100 mg twice a day) before June 2001 in three Italian Centres of Infectious Diseases. The inclusion criteria were: no previous exposure to LPV/r; previous experience of at least one protease inhibitor (PI)-based regimen; and an HIV-RNA level greater than 3 log10 copies/ml at the initiation of LPV/r (baseline). At baseline, patients' demographic characteristics and data regarding the number of antiretroviral regimens and of PI, nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) changed were recorded. HIV-RNA levels were measured using a branched chain DNA technique (Chiron, Inc., Emeryville, California, USA; detection limit 50 copies/ml) and CD4 cell counts were measured using the elite flow cytometer (Coulter Corporation, Miami, Florida, USA); both these parameters were collected at baseline and at least every 3 months. AIDS events, drug-related toxicities, drug discontinuations and deaths were also recorded throughout the observation period.
The primary endpoint of our study was the proportion of patients with HIV-RNA levels less than 50 copies/ml after 4 years of follow-up by intention-to-treat (ITT) analysis. Secondary endpoints included the on-treatment proportion of patients with HIV-RNA levels less than 50 copies/ml, in which patients discontinuing LPV/r for any reason were excluded. Moreover, the CD4 cell count outcome, defined as the mean change of CD4 cell counts from baseline, was evaluated by t test.
The study involved 167 HIV-infected, HAART-experienced patients. The mean age was 38 years (range 22-63) and 110 were men (65.9%). Sixty-nine subjects were at CDC stage C; the median CD4 cell nadir was 90 cells/ml (2-455) and the median HIV-RNA peak was 5.11 log10 copies/ml (3.41-6.34). Patients changed a median of nine antiretroviral regimens (three to 16) and three PI (one to five) before starting LPV/r. At baseline, the median CD4 cell count was 171 cells/ml (2-835) and the median HIV-RNA level was 4.55 log10 copies/ml (3.08-6.34). The median duration of previous antiretroviral regimens and of HAART were 7.7 (2.3-11.1) and 4.6 years (2.3-6.2), respectively. Most of patients (n = 121, 74.0%) started LPV/r in combination with two NRTI; 46 (26.0%) combined LPV/r with NRTI plus PI/NNRTI (eight PI and 38 NNRTI).
By ITT analysis, after 4 years of follow-up 64.8% of patients achieved an HIV-RNA level of less than 50 copies/ml, with corresponding on-treatment results of 83.5%.
A substantial increase in the CD4 cell count was found throughout the study. In particular, the mean increase was 161, 180, 168, and 147 cells/ml after 1, 2, 3 and 4 years of follow-up (P < 0.01 at each timepoint), respectively.
A total of 66 patients (39.5%) discontinued LPV/r: 33 for toxicity (19 for gastrointestinal symptoms, 12 for an increase of lipids levels, and two for an increase of liver enzyme levels), 15 for HAART simplification, 11 for lack of virological response, and seven for low compliance. Fourteen patients (8.8%) developed an AIDS event and eight (4.8%) died.
In our study, LPV/r-containing regimens provided a potent and durable antiretroviral response also in HIV-infected, HAART-experienced subjects. At present, data on the long-term virological efficacy of this drug are available only for HIV-infected naive patients [7]. Our results in a clinical setting confirm both the virological and immunological efficacy of LPV/r, previously reported in studies with a shorter follow-up [6,8].
Less than 20% of patients included in our study discontinued LPV/r for drug-related toxicities, mainly gastrointestinal symptoms. Few patients stopped LPV/r for a lack of virological response; this finding can be caused by the significant increase in CD4 cell counts also observed in these subjects.
In summary, this long-term follow-up study on HAART-experienced patients treated with LPV/r demonstrated a durable HIV suppression and a substantial increase in CD4 cell counts over 4 years. These data support the use of LPV/r in HIV-infected patients also as part of a salvage regimen.
Sponsorship: This work was supported by a grant from the Italian Institute of Health AIDS Project (no. 50D.06).
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