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Update on Kaletra Resistance
Written by Jules Levin
  Abbott researchers have been reporting that resistance to Kaletra cannot be found in patients with viral rebound in their studies. The last report at IAS during the Summer was out to 60 weeks of follow-up. They reported a 96-week update at ICAAC (December 2001). They looked at 653 patients in study M98-863 which was a large international study comparing Kaletra to nelfinavir in treatment-naive patients, where everyone also received d4T+3TC. This report also discusses preliminary research findings by Abbott on how many genotypic mutations and how much phenotypic resistance reduce or prevent response to Kaletra.
In this study at week 60, 74% had <400 copies (ITT NC=F) in the patients receiving Kaletra and 62% had <400 in the nelfinavir group (NFV). 64% in the Kaletra group had <50 copies compared to 53% in the NFV group. Lipids tend to become elevated on Kaletra. Triglycerides were more likely to be elevated in the Kaletra patients (grade 3/4 elevations: 11% vs 2%). 326 patients received Kaletra and 327 NFV. Diarrhea can occur (12-17%), particularly during the first few weeks of therapy, and often lift after the first few weeks of therapy. As well, asthenia (fatigue or weakness) also can occur (11%-15%).
In this resistance study, blood samples from all patients with viral load >500 once during the period from week 24 through week 96 while on their assigned-treatment were submitted for resistance testing. A total of 74 Kaletra-treated and 113 NFV-treated patients had at least one blood sample submitted for resistance testing. For patients with VLs >500 during this period, the latest sample for which the genotype test result was available was used for this analysis, unless PI resistance had been seen at an earlier timepoint (which obviously occurred only for NFV). Genotypic and phenotypic testing was performed by Virologic.
Blood samples from 51 of 74 Kaletra patients and 96 of 113 NFV-patients could be amplified for resistance testing. None of the 51 Kaletra-treated patients with available genotype results showed genotype resistance to Kaletra. The absence of resistance to Kaletra was confirmed by phenotypic testing in all Kaletra-treated patients for whom a phenotypic result was available (46/51 blood samples). 41 of the 96 NFV-treated patients with available genotypic results showed genotypic resistance to NFV. The genotype resistance profile before starting therapy in this study was available for 35/41 NFV-treated subjects who had resistance during the study. None of these patients had the signature NFV mutations before starting therapy (D30N, or L90M). Genotypic resistance was defined for NFV as the development of a D30N and/or an L90M. Kaletra genotypic resistance was defined as the development of mutation at any primary or active site in the protease (8, 30, 32, 46, 47, 48, 50, 82, 84, 90). Also, 3TC resistance was seen significantly more often in the NFV patients.
  Abbott researchers mentioned that two factors potentially related to the development of resistance include the exposure to viral replication after viral rebound and adherence. They looked at the 74 Kaletra and 113 NFV viral failures and found adherence was about the same (72% in the NFV group vs 65% in the Kaletra group). But adherence was higher in the responders than in the nonresponders in the study. Study authors also reported there was no statisyically significant difference between the treatment groups when looking at various measures of exposure to viral replication.
3TC resiatance in the NFV group was related to the duration of time with viral load >400. But in the Kaletra group the emergence of 3TC resistance was not related to any of the measures used to evaluate exposure to viral replication, which included viral load at the time of genotype testing, total days with >400, and viral load AUC. Researchers said similar findings have been seen in other studies. And they suggested that the difference in the rate of PI resistance development may reflect the higher IQ observed with Kaletra-treated patients than in the NFV-treated patients. IQ is the Inhibitory Quotient (Ctrough/IC50 ratio); Ctrough is the drug level in blood at the end of the dosing period (12 hours) and the IC50 is how much drug is needed to suppress 50% of viral replication. So in essence, this ratio is a measure of how much more drug is in the blood than is needed to suppress viral replication. (editorial note: I do not understand how this explanation explains the findings that Kaletra resistance cannot be found. But this finding has been consistently reported out to 96 weeks now. The question is-- what are the implications of these findings? Another key question currently under investigation is what PI regimen could be used to successfully treat Kaletra viral failures.
This information was initially reported at the Resistance Workshop two years ago in 2000, but is worth repeating and Abbott reported this again at ICAAC (poster 1925). They looked at study M98-957, which is a study of Kaletra in combination with efavirenz and NRTIs, in patients with experience with multiple PIs. 57 patients received Kaletra (lopinavir 400mg/ 100mg ritonavir; 3 coformulated capsules) twice daily for the first 13 days of the study. On day 14, 28 patients increased their Kaletra dose to 4 capsules (533/133). 86% of patients had previously used IDV, 77% RTV, 72% SQV, and 58% NFV. On average each patient used 3 PIs previously. Over 90% of patients had previously used AZT, d4T and 3TC; 18% had used abacavir. And patients were NNRTI-naive. Before starting the study patients on average had 5-fold Kaletra resistance, 10-fold IDV resistance, 20-fold NFV resistance, 28-fold RTV resistance, 6-fold SAQV resistance, and 2-dfold Amprenavir resistance.
Kaletra levels achieved with the 400/100 mg dose are reduced by 30% (trough 33%, AUC 25%) when efavirenz is combined with it. The 533/133 dose is recommended since this provides similar Kaletra levels as the 400/100 dose without efavirenz.
After week 72, 67% had <400 (ITT, missing=failure) and 61% had <50 copies.
This is the key resistance information reported at ICAAC. On average, if a patient had >40 fold (n=8) Kaletra resistance before starting therapy in this study only 25% achieved <50 copies at week 72. If the patient had 10-40 fold resistance (n=15), 60% had <50 copies, and if patients had on average <10 fold Kaletra resistance (n=27) 89% had <50 copies.
If patients had 8-10 genotypic mutations (n=6) 33% had <50 copies. If the patients had 6-7 mutations, 62% had <50 copies, and when 0-5 mutations were found 87% had <50 copies.
(editorial note: The numbers of patients in these analyses are small, but this analysis does offer some guideline for evaluating a patient's ability to respond to Kaletra. The fact that patients were NNRTI-naive and also received efavirenz certainly helped their response and ability to achieve undetectable viral load. It is difficult to sort out exactly how much Kaletra and efavirenz each contributed to the overall ability to achieve undetectable, but researchers expressed at the Resistance Workshop in 2000 that patients with up to 6-7 mutations ought to be responsive to Kaletra without using efavirenz. Of course the fewer the number of PI mutations the better the response should be. They also seemed to feel that patients with up to 20-fold phenotypic resistance to Kaletra should be responsive to Kaletra without EFV. All new drugs for patients with resistance coming to market should have this sort of research performed. I think the FDA package insert says the cutoff for Kaletra resistance is 10-fold phenotypic resistance, but perhaps this is too conservative.
If you would like to read the entire NATAP reports from the Resistance Workshop in 2000 on Kaletra here are links to the 2 articles. They describe in much more detail the findings reported and the discussion by researchers about the findings:
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