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  International AIDS Conference
July 13-16, 2003, Paris
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Kaletra Update: Kaletra+Tenofovir+3TC Once Daily Study; Updated PHHS Guidelines on Preferred Regimens for First-Line Therapy
Reported by Jules Levin
  Researchers reported preliminary results at the IAS Conference of a study examining the use of Kaletra once daily. Here is the brief summary of the results reported in the poster followed by background provided by the poster at the conference and detailed results reported. As well, several additional posters on Kaletra were reported at the IAS Conference with interesting information. This report summarizes key information regarding Kaletra in the posters at the conference. Of note, after following over 500 patients for an average of about 2 years, Abbott still reports that they do not see any protease inhibitor resistance in their studies in patients after viral failure occurs while on Kaletra. See discussion just below regarding this resistance data. As well, Abbott reported at this conference 4 year follow-up on patients in the longest study of Kaletra. This was a phase II study of 100 patients. After 4 years 72 remain in study and 70% of patients have <50 copies/ml. An interesting analysis of CD4 count response by patients in this study is discussed below.
SUMMARY OF KALETRA ONCE DAILY STUDY. Kaletra (LPV/r 800/200 mg) once daily produced a slightly higher LPV C max (peak drug level) , similar AUC (total drug level during 24-hr dose period) and lower C trough (lowest drug level before taking next dose) vs. Kaletra (LPV/r 400/100 mg) twice daily. These study results report the viral load decline after 4 weeks which may give a preliminary suggestion of viral effectiveness and viral load declines were similar between regimens. No correlation between Week 4 IQ (inhibitory quotient) and viral load decline was observed in these ARV-naive subjects.
When combining data with that from a previous pilot study, median LPV IQ was 47 for once daily and 94 for BID. LPV IQ with LPV/r once daily compares favorably to other protease inhibitor regimens dosed once daily. Efficacy and safety of Kaletra LPV/r twice daily and once daily dosing will be assessed as study participants are followed for a longer duration of 48+ weeks in this study.
NEW PHHS TREATMENT GUIDELINES. Of note, an update was issued at the IAS Conference for the Public Health and Human Services HIV Treatment Guidelines. The PHHS panel changed the Guidelines to list only two preferred regimens for first-line therapy for treatment-naive patients, and here are key excerpts. The full updated 96-page Guidelines can be found at the NATAP website, where a pdf version can be downloaded to your computer and printed out. The Panel recommends efavirenz in combination with lamivudine and zidovudine, tenofovir, or stavudine as preferred first-line NNRTI-containing regimens in antiretroviral naive patients. An exception to this recommendation will be in pregnant women or women at risk for pregnancy, as efavirenz has been associated with significant teratogenic effects in nonhuman primates. The panel recommends Kaletra (lopinavir/ritonavir) in combination with (zidovudine or stavudine) plus lamivudine as preferred PI-based regimens. The new Guidelines list alternative PI regimens. There is little experience with the use of lopinavir/ritonavir in pregnant women. Among all the currently marketed PIs, nelfinavir has the most safety experience in this population. The panel recommends that a 3-NRTI regimen consisting of abacavir (Ziagen) in combination with (zidovudine or stavudine) plus lamivudine may be used as an alternative to an NNRTI-based or a PIbased regimen in antiretroviral-naive patients. This regimen should not be initiated in patients with baseline viral load >100,000 copies/mL. The panel recommends a combination of lamivudine with zidovudine as the 2-NRTI combination of choice as part of a combination regimen. Combination of lamivudine with stavudine or tenofovir may be used as alternative. In the section, on what not to use, the panel recommends not to use hydroxyurea. Hydroxyurea appears to enhance the antiviral activity of didanosine. However, it also promotes the toxicity of didanosine with increased rates of peripheral neuropathy and pancreatitis. An additional concern is the lack of CD4 response with hydroxyurea that presumably reflects the drugs cytotoxic effect.
BACKGROUND ON KALETRA. Here is background information provided by Abbott in their poster on the once-a-day Kaletra study and other posters at the conference. The study, which is described below, uses double the dose of Kaletra taken once a day. Preliminary responses to the once a day and twice a day regimens are reported and discussed below. The study was an open-label, multiple-center, non-fasting study in 190 HIV-infected individuals.
Lopinavir (LPV) is an HIV protease inhibitor that is co-formulated with ritonavir (RTV), which functions as a pharmacokinetic enhancer, and is marketed as Kaletra (LPV/r).
The approved adult dose of LPV/r is 400/100 mg twice daily (BID) taken with food, and used in combination with other antiretrovirals (ARVs). Twice daily (BID) antiretroviral HIV regimens including Kaletra provide potent and durable viral suppression. A once daily regimen using Kaletra may offer increased convenience for treatment-naive patients.
RESISTANCE. At the standard 400/100mg twice daily dose used, Kaletra (LPV) mean pre-dose concentration (C trough) exceeds protein binding-adjusted IC 50 for wild-type HIV by 75-fold (inhibitory quotient or IQ >75). This high ratio of LPV trough concentrations to IC 50 (known as the inhibitory quotient or IQ) appears to provide a significant pharmacologic barrier to emergence of viral resistance in antiretroviral (ARV)-naive patients. In over 500 ARV-naive patients enrolled in Phase II/III trials with LPV/r for a median duration of 97 weeks (range, 0-250 weeks) no evolution of genotypic or phenotypic resistance to LPV has been observed.
In Study M98-863 Kaletra was compared to Viracept (nelfinavir). LPV/r showed superior antiviral efficacy in a randomized, double-blind Phase III clinical trial (Study M98-863) comparing Kaletra to nelfinavir with d4T/3TC in ARV-naive patients. In a time to loss of virologic response curve 79% of patients receiving Kaletra maintained viral suppression by week 96 in this study compared to 58% of patients taking nelfinavir regimen.
Through 96 weeks of therapy, no evidence of primary resistance to LPV (defined as any primary or active site mutation) was detected in any of 51 Kaletra-treated patients with detectable viral load for whom genotype was available. In contrast, 48% of isolates from nelfinavir-treated patients displayed primary resistance to nelfinavir (emergence of D30N and/or L90M) or displayed substantially reduced (> 6.8-fold) susceptibility to nelfinavir in the absence of either primary mutation. Moreover, through 96 weeks, patients on LPV/r demonstrated a significantly lower cumulative probability of resistance in protease and reverse transcriptase. 74 patients (74/326,23%) taking Kaletra had HIV-RNA >400 copies/ml, and 113 patients (113/327, 35%) taking nelfinavir had >400 copies/ml. 51/74 patients taking Kaletra and 96/113 (85%) of patients taking nelfinavir had genotype test available. 0% taking Kaletra had PI resistance vs 48% (46/96) taking nelfinavir. Regarding 3TC resistance, 37% (19/51) of patients taking Kaletra vs 82% (79/96) of patients taking nelfinavir had 3TC resistance.
4-YEAR FOLLOW-UP OF KALETRA. At the IAS Conference Abbott reported the 4-year follow-up of treatment-naive patients in the longest study of Kaletra so far. The results show that Kaletra is potent and durable in its antiviral effectiveness. The patients in the study show continued high response rate (70% with HIV RNA <50 copies/mL by intent-to-treat analysis) >4 years when dosed with stavudine (d4T) and lamuvidine (3TC) during ongoing studies in ARV-naive, HIV-infected subjects reflects the durability of the twice daily regimen. 100 patients originally started this study and 72 remain in the study. The mean increase in CD4 count for the patients in this study is 500 cells. Of note, 59 of the 72 patients have shown an increase in CD4 count of 500 cells or more. CD4 counts have continued to increase through the 4 years. For patients on the study at week 216, increases in CD4 cell count were largest during the first 48 weeks of study (230 cells). An increase of 141 cells was observed during the fourth year of study (between weeks 156-216) following annual increases of 56 and 72 cells during the second and third years of study (Weeks 48-156). Also of note, patients starting this study with <50 CD4s had a mean increase of 489 cells over the 4 year follow-up. GI upset is the most common side effect associated with Kaletra. 27% of patients reported diarrhea, but Abbott reports in the poster that the prevalence reported by patients at week 216 is 2%. Kaletra is also associated with elevations in cholesterol and triglycerides. In this study 22% of patients reported incidence of cholesterol >300 and 22% reported triglycerides >750 mg/dL during the 216 weeks. The poster reports 7% of participants discontinued due to drug-related adverse events. Of interest, through 216 weeks of follow-up, no protease inhibitor resistance mutations have been observed.
Background. A once daily (QD) regimen including LPV/r may offer an advantage with regard to convenience while maintaining antiviral potency in ARV-naive patients.
Results from Pilot Study 056 in which ARV-naive, HIV-infected adults (N=36) received LPV/r 800/200 mg QD and 400/100 mg BID with the nucleoside agents, d4T and 3TC given BID, showed that:
--LPV/r 800/200 mg QD produced steady-state LPV C max and AUC similar to 400/100 mg BID
--Median LPV C trough over 48 weeks exceeded the protein binding-adjusted IC 50 of wt-HIV by 40- and 84-fold in the QD and BID regimens, respectively
--LPV C trough was more variable with QD dosing
--The safety and efficacy of QD and BID regimens were similar through 72 weeks in ARV-naive subjects
--The LPV IQ after LPV/r QD dosing appears to compare favorably to that of other QD protease inhibitor-based regimens. IQ is a measure of the level of drug attained in blood after administering a drug compared to how much is needed to inhibit virus replication by 50%. Inhibition of virus replication by 50% is a standard lab measure of a drugs potency and how much drug is needed to suppress the virus. In sum, the IQ evaluates if a patient has adequate levels of drug in the blood to inhibit the virus from replicating.
ONCE A DAY STUDY compares Kaletra taken once a day at dose of 800mg lopinavir boosted by 200 mg of ritonavir vs 400 mg lopinavir boosted by 100 mg ritonavir.
In this study analysis the PK and initial antiviral activity of Kaletra in a once-a-day regimen were assessed.
Treatment-naive HIV+ individuals were randomized Kaletra, dosed with food (N=190) as 800/200 mg once-a-day or 400/100 mg BID, the standard dose of Kaletra. Each treatment arm also received tenofovir (300 mg) and FTC (200 mg), both of these drugs are also taken once-a-day. 115 patients received Kaletra 800/200mg vs 75 who received Kaletra 400/100mg. 24-hour PK sampling was conducted in a subset of 24 patients taking the once daily regimen vs 13 taking the twice daily regimen. Average CD4 count was about 220, and avg viral load was 50,000 copies/ml.
PATIENT CHARACTERISTICS. The particiapants were mostly men (93/115 in once daily regimen and 56/75 in the twice daily regimen. Age- 39 yrs. About half of participants were White, one-third were Black, and 10% Hispanic.
An inhibitory quotient (IQ= pre-dose levels or C trough /protein binding-adjusted IC 50 for wt-HIV) was to be estimated for each subject.
Plasma (blood) levels of LPV/r were measured over a dosing interval at week 4 (QD N=24, BID N=13). Pharmacokinetic (PK) parameters were log transformed and compared using ANOVA.
In the PK substudy, Kaletra (LPV/r 800/200 mg) once daily vs. Kaletra 400/100 mg BID produced mean SD:
--LPV C max of 11.8 3.7 vs. 9.7 4.1 g/mL (p=0.07)
--AUC 24 of 154.5 60.5 vs. 182.2 84 6 g.h/mL (p=0.4)
--C trough of 3.0 1.8 vs. 6.5 3.8 g/mL (p=0.01).
--Despite differing background NRTI regimens, PK results were very similar between Study 418 and Pilot Study 056 for both the LPV/r QD and BID regimens.
Median viral load (VL) change from baseline to week 4 was similar for QD (-2.1 log 10 c/mL) vs. BID (-2.0 log 10 c/mL). In these ARV-naive subjects, no significant relationship was noted between Week 4 VL decline and LPV IQ (r=0.005, p=0.43, N=132).
No difference in laboratory abnormalities through 4 weeks was noted.
Kaletra PK was similar to a previous study in ARV-naive subjects of QD (N=17) vs. BID (N=19) + d4T and 3TC (p>0.5 for LPV C max , AUC and C trough ).
Combining both studies, QD (N=41) vs. BID (N=32) LPV point estimates (90% CI) were 1.22 (1.05, 1.40) for C max , 0.90 (0.75, 1.09) for AUC and 0.37 (0.26, 0.53) for C trough .
Combining all usable IQ data for QD (N=105) and BID (N=66), median [interquartile range] was 47 [range 16-84] vs. 94 [range 55-30]. Despite lower IQ in QD vs. BID, no correlation was noted in QD subjects between IQ and 4-week VL decline (p>0.9).
The authors concluded that Kaletra (LPV/r 800/200 mg) once daily produced a slightly higher LPV C max, similar AUC and lower C trough vs. 400/100 mg BID.
LPV PK was similar as part of a regimen containing TDF and FTC vs. d4T and 3TC.
Median lopinavir IQ was 47 for QD and 94 for BID. Week 4 VL declines were similar between regimens.