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  AIDS 2002 Barcelona
Barcelona, Spain July 7-12 2002
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Kaletra Studies at Barcelona
Reported by Jules Levin, contributions by David Margolis, MD, University of Texas Southwestern Medical Ctr
  -Once a day
-Response and genotypic resistance
-3 year follow-up
-in advanced HIV
-with methadone
-interactions with amprenavir !!!
-nevirapine reduces Kaletra blood levels, consider dose increase
-effect on cholesterol & triglycerides: nelfinavir vs ritonavir boosted PI regimens
-nuke sparing regimen: Kaletra + 1000mg saquinavir
Kaletra Once A Day: small pilot study
In a small study of 38 ARV-naive patients, Feinberg [TuPeB4445] suggested that Kaletra could succeed as a once-a-day PI. LPV/r (Kaletra) 800/200mg QD was compared to 400/100mg BID with d4T/3TC BID. A reasonably mixed patient population with median baseline VL 4.7 log10 copies/mL (50,000) and CD4 cell count 264 cells/mm3 were studied for 72 weeks. Tolerability and AEs were comparable between the two arms. At Week 72, 83% and 82% of patients randomized to LPV/r QD and BID, respectively, had VL<50 copies/mL (on treatment) and 74% and 58%, respectively, had VL <50 copies/μL (intent-to-treat [NC=F], p=0.31). Although the pill burden (6 Kaletra capsules at once) may present a challenge, if this boosted PI is used in initial therapy this study provides proof-of-concept for once-a-day therapy.
Kaletra Expanded Access Experience in Spain
Analysis of the first 137 patients recruited during the expanded access program in an HIV/AIDS reference centre in Spain. Only subjects with significant past exposure to all three different antiretroviral drug families and failing their current regimens were chosen. A total of 104 and 68 subjects completed, respectively, 6 and 9 months of follow-up. Average HIV viral load before beginning Kaletra was 11,000 copies/ml and CD4 count was 285. Overall, in an Intent-To-Treat (including patients who withdrew from study therapy) analysis 61.2% and 57.8% of subjects showed a significant virologic response (defined as >1 log reduction in plasma HIV-RNA and/or to less than 500 HIV-RNA copies/ml) at 6 and 9 months, respectively
In on-treatment (patients who stayed on therapy) analysis 68.8% and 70.6% of patients showed virological response at 6 and 9 months, respectively. Adverse effects leading to drug discontinuation (mostly GI intolerance) occurred in 6.5% of subjects. Triglyceride levels significantly increased after starting Kaletra (+70 mg/dl; p=0.04) while cholesterol levels remained stable (+7.7 mg/dl; p=0.7).
Genotypic testing at baseline showed a median number of PI mutations of 4 (0 to 12). Overall, 45% of subjects harboured ≥5 PI mutations. Attainment of plasma HIV-RNA <500 copies/ml occurred in 88% of subjects with < 5 PI mutations but only in 48% of those harbouring >5 PI mutations (p<0.001). Baseline mutations at codons 71 and 82 were associated with a lower response to Kaletra.
[MoPeA3017] C. de mendoza Instituto de Salud Carlos III, Madrid, Spain
Immune Reconstitution After 3 Years on Kaletra
Alan Landay [TuPeB4439] presented 3 year follow-up on immune reconstitution in antiretroviral-naive patients treated with Kaletra. Baseline average CD4 count was 391 and viral load about 80,000. Using ITT analysis (NC=f) 75% had <400 copies after 3 years. At week 156, 78/100 pts remained on study drug. At week 156 the median CD4 cell count had risen to 596. Of 17 patients with CD4 < 50 cells/μl, 14 were > 200 cells/μl, 10 > 350 cells/μl, 3 > 500 cell/μl at week 156 or their last observed value. Of 19 patients with 50-199 CD4s at baseline 32% (6) achieved >500 CD4 count. As we have seen before, considerable immune reconstitution is possible if viremia is durably suppressed.
Kaletra in Treatment-Naive Patients with Advanced HIV
Fatkenheuer [TuPeB4447] studied the efficacy of Kaletra in patients with severe immune deficiency and/or high viral load in clinical practice. This was an observational, prospective study of patients treated with Kaletra and two nukes. Patients had <100 CD4s, or HIV viral load of >100,000, or an opportunistic infection. 86 patients have been included (84% male, 16% female) and 57% were CDC stage C(more advanced). Average viral load was 321,561 copies and CD4 cells were 90. Average CD4 count was 260 after month 6 on therapy. 69% (23/33) achieved HIV- RNA <400 copies/mL at month 3 and 87% at month 6 (13/15; on- treatment analysis). No opportunistic infections occurred up to month 6. As expected increased triglycerides (from median 150mg/mL to 190mg/mL) and total cholesterol (from median 160mg/mL to 190mg/mL) was observed at month 6.
Kaletra Did Not Affect Methadone
Rappaport [TuPeB4539] reported on the effect of methadone on patients taking Kaletra. Kaletra has been shown to reduce the AUC (blood levels) of methadone by 47% in healthy volunteers; however, the clinical significance of this interaction has not been well studied. Patients were on a stable methadone dose for at least 1 month prior to starting Kaletra. Patients were excluded if they received medications known to alter methadone clearance within 2 weeks of Kaletra. Methadone dose requirements and opiate withdrawal symptoms were reviewed over 4 weeks after starting Kaletra. 27 patients were evaluated, of which 8 were considered ineligible mainly due to not being on a stable methadone dose. The average maintenance methadone dose was 95 mg/day (range, 40 to 130) for 38 weeks (range, 5.0 to 467.4) before starting Kaletra. No methadone dose changes or withdrawal symptoms were observed during the 4-week evaluation period. Viral load was 70,000 on average for the patients prior to starting Kaletra and Cd4s were 175. The average viral load reduction for the first 12 weeks on Kaletra was -2.49 log and the average CD4 increase was 80; showing methadone did not prevent a good response to Kaletra overall in these patients; 57% achieved <400 copies. One patient experienced nausea and vomiting that led to discontinuation of Kaletra after 2 days; however, no adverse events were reported for the remaining patients. As a precaution, it is still recommended to monitor for opiate withdrawal even though none was observed in this study.
The Pharmacokinetic interaction of Kaletra and Amprenavir
Reynolds [TuPeB4560] reported interaction between Kaletra (lopinavir 400mg + ritonavir 100mg) and amprenavir when used combination. It appears as doctors are using amprenavir with Kaletra in clinical practice and there have been conflicting reports of a pharmacokinetic (PK) interaction with these drugs. At least two studies have demonstrated a 50% reduction in APV when used at 600 mg twice daily in combination with Kaletra (400/100 mg bd) compared to APV boosted by ritonavir (600/100 mg bd), leading to a recommendation to increase the dose of APV to 750 mg bd when given with Kaletra. However, other studies have indicated that APV concentrations were not apparently reduced when given with Kaletra and an NNRTI. In addition, the interaction would appear to be two-way as lower Kaletra concentrations have been reported in the presence of APV, both in the absence and presence of an NNRTI.
The Liverpool TDM Service (David Back) has included APV and LPV plasma concentration monitoring since early 2001. The data set has been analysed to determine the nature of this PK interaction in patients requesting TDM in the UK by investigating both APV and LPV concentrations. Only adult patients where full details of the antiretroviral regimens were available were included.
  The effect of adding Kaletra to APV/r resulted in a significant decrease in the median APV plasma concentration (p=0.05) despite an increase in APV dose. In this small patient study group, the addition of an NNRTI further reduced the median APV concentration (p=0.03).  
  Kaletra median plasma concentrations were significantly reduced by adding APV (p=0.005), however the presence of an NNRTI had a lesser effect (p=0.22). The study authors concluded this is a complex PK interaction and given the marked interpatient variability highlights the potential importance of concentration monitoring (TDM).
Nevirapine Reduces Kaletra, Consider Kaletra Dose Increase
Bertz from Abbott reported on the affect of nevirapine on Kaletra blood levels and recommended dosing of Kalwtra. Lopinavir/ritonavir (LPV/r) also known as Kaletra is metabolized by CYP3A. The nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) is a CYP3A inducer, and has been shown to reduce LPV concentrations during coadministration with LPV/r in pediatric HIV-infected subjects (ages 6 mo-12 yr). 23 HIV-infected adults with previous PI treatment (n=23), receiving LPV/r 400/100 mg BID + NVP 200 mg BID + nucleoside analogs (NRTIs) in clinical trials, participated in this PK substudy. Steady-state plasma concentrations of LPV/r were obtained over a 12 hour dosing interval. Coadministration of LPV/r with NVP resulted in a decrease in both LPV and ritonavir concentrations. Preliminary analysis showed that the mean LPV AUC (blood level) was 26% lower (p<0.05) and Cmin was 53% lower (p<0.01); mean Cmax was 15% lower (p>0.10). Results were consistent with those observed previously in pediatric subject. A dose increase of LPV/r to 533/133 mg (4 capsules) BID should be considered during concurrent NVP use, where reduced susceptibility to LPV is clinically suspected.
Effect of Ritonavir-boosted Protease Inhibitor Regimens and Nelfinavir on Cholesterol & Triglycerides
McComsey and Agouron [ThPeB7319] reported a retrospective review of patients comparing cholesterol and triglycerides responses after starting a PI regimen boosted with 100 mg of ritonavir (indinavir, Kaletra, or amprenavir) and Viracept (NFV) therapy.
74 and 67 were on NFV and boosted-PI respectively (62 on Kaletra). Both groups had 20% women. Median age was similar in both groups (40 and 38 y, respectively). NNRTI were received by 9% and 6% in the NFV and boosted-PI groups, respectively. Median duration of prior ARV was 42 months and 50 months, respectively. Baseline cholesterol were >220 mg/dl in 14% and 10% of subjects on NFV and boosted-PI, respectively. Baseline triglycerides were >160 mg/dl in 43 % and 59 % of subjects on NFV and boosted-PI, respectively. Only one (on NFV) was receiving a lipid-lowering agent.
In the NFV group, cholesterol increased from baseline by 11.5% (p=0.05) at 3 months, and by 14% (p<0.001) at 6 months; triglyceride did not change significantly (+7%, p=0.94) at 3 months; +10%, p=0.84) at 6 months). In the boosted-PI group, cholesterol increased by 15% (p=0.003) at 3 months, and by 16%(p< 0.001) at 6 months; triglycerides increased by 71%(p=0.001) at 3 months, and by 63% (p=0.001) at 6 months. After 3 and 6 months of therapy, changes in triglycerides were significantly higher in the boosted-PI group, compared to changes in the NFV group (p=0.03 and 0.05 at 3 and 6 m, respectively). Changes in cholesterol between groups were not significantly different in this study. RTV-boosted PI, not NFV, is associated with significant increase in triglyceride levels in this study. In the contrary, both PIs affected cholesterol levels. The metabolic complications of each PI should be assessed separately.
Kaletra + 1000mg Saquinavir Without Nukes
Staszewski [TuPeB4474] reported preliminary results on 33 of 63 patients from a small pilot study of a nuke sparing regimen of Kaletra plus 1000 mg of saquinavir twice daily without nukes. These were ART-experienced patients at this German clinic who had experienced treatment failure and were resistance to nukes (by genotype test), or intolerant of nukes, and sensitive to protease inhibitors (by genotype). Patients were switched from their regimen to this new one. Some patients were already on Kaletra. 11 patients responded to virologically to previous therapy but switched regimen due to toxicity/intolerance. After an average 29 weeks, 24 patients stayed on therapy and 7 discontinued due to virologic failure. By week 14 patients reached their greatest viral load reduction (nadir). 6/33 (18%) rebounded after reaching their viral load nadir. But at the 14 week nadir point 73% (24/33 achieved 2 log reduction or more; 82% (27/33) had <400 copies at 7 weeks, and 19/33 (56%) had <50 copies at 13 weeks. Patients with 200 CD4s responded better than those with 50 CD4s, on average. The preliminary results of this study suggest that this nuke sparing PI regimen may be effective for certain patients. It's combination with Tenofovir and/or T-20 may also be useful.