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Update on Kaletra Resistance
Written by Jules Levin
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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.
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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.
GENOTYPIC AND PHENOTYPIC CORRELATES OF KALETRA VIRAL LOAD RESPONSE IN
MULTIPLE-PI EXPERIENCED PATIENTS
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.
EFAVIRENZ REDUCES KALETRA BLOOD LEVELS.
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.
RESPONSE MEASURED BY PHENOTYPIC AND GENOTYPIC RESISTANCE BEFORE THERAPY
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:
www.natap.org/2000/4thspain/rpt01spa_abt378corr_061500.htm
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