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Low Nelfinavir Blood levels Causes Treatment failure
  "Nelfinavir plasma concentrations in patients experiencing early failure with nelfinavir-containing triple combinations"
summary: Virological failure to protease inhibitor (PI)-based antiretroviral regimens is often not explained by the selection of PI resistance mutations. The role of low PI plasma levels in treatment failure was assessed in 30 patients failing nelfinavir-containing triple combinations. Approximately a third of the patients showed sub-therapeutic nelfinavir plasma levels. More than two-thirds of them had no drug resistance mutations, suggesting that insufficient nelfinavir levels contributed to treatment failure.
Virological failure to highly active antiretroviral therapy has been associated with low drug potency, the selection of drug-resistant variants, poor adherence to medication, or low drug exposuree. Overall, up to 35% of patients taking protease inhibitors (PI) without ritonavir boosting might have inadequate drug concentrations.
In a previous study, we demonstrated that virological failure in drug-naive patients taking nelfinavir as part of a first PI-based triple combination was associated with primary PI resistance mutations in only 27% of patients. In order to assess whether their virological failure could be related to low nelfinavir exposure, nelfinavir plasma trough concentrations were determined in samples collected at the time of viral rebound.
Thirty patients were included in the study. All patients were taking nelfinavir 1200 mg twice a day plus two nucleoside reverse transcriptase inhibitors. They were seen regularly in the outpatient clinic every 3 months. Blood samples were drawn before the morning dose intake (trough concentration). Nelfinavir plasma concentrations were determined using a validated high-performance liquid chromatography method with ultraviolet detection. Nelfinavir trough concentrations above 0.7 [mu]g/ml were considered to be therapeutic, in accordance with previous reports. HIV genotyping was performed using an automatic sequencer (ABI Prism 3100, Applied Biosystems, Foster City, CA, USA) for detecting drug resistance mutations.
Treatment failure occurred at a median time of 13 months (4-32) after initiating nelfinavir, and the median plasma HIV-RNA level at the time of viral rebound was 4180 copies/ml. Out of 20 patients for whom both nelfinavir plasma levels and HIV genotyping were available, seven (35%) were found to have sub-therapeutic nelfinavir plasma levels. Of note is the fact that in six patients those levels were undetectable, and in one were 0.5 [mu]g/ml. Primary PI-associated resistance mutations were found in only one of the seven individuals (14%) with sub-therapeutic nelfinavir concentrations, whereas they were found in four out of 13 patients (30%) with adequate nelfinavir concentrations. It should be pointed out that drug resistance mutations were absent either in the protease or the reverse transcriptase genes in five out of seven patients with sub-therapeutic nelfinavir concentrations.
In line with other recent studies, our results highlight the importance of keeping adequate PI plasma levels in order to maintain a maximal HIV suppression. Sub-therapeutic nelfinavir plasma levels could explain the virological failure in approximately a third of our patients. Given that the majority of these individuals had undetectable nelfinavir plasma concentrations, a lack of adherence to the medication was the most likely cause of their sub-therapeutic drug levels. This hypothesis was supported by the lack of recognition of nelfinavir-associated resistance mutations in these individuals. Although other causes such as impaired gut absorption or drug interactions could also been involved, the lack of recognition of any nelfinavir trace in our patients strongly suggests that they were not taking the prescribed medication.
Whereas low nelfinavir plasma levels represented the only identified factor involved in treatment failure in 20% of our patients, the presence of nucleoside reverse transcriptase inhibitor resistance mutations probably contributed to failure in another 10% of cases. It has been well established that the interplay between low plasma drug levels and resistance mutations may finally lead to virological failure. Incomplete HIV suppression in individuals with sub-therapeutic PI levels sets the ground for the selection of mutations. In a small subset of our patients neither nelfinavir resistance nor insufficient nelfinavir plasma levels could explain virological failure. In this situation, however, it may be argued that a single determination of nelfinavir plasma levels could be not enough to ascertain a good compliance for a long period of time.
In summary, our results support the usefulness of measuring drug levels in patients on virological failure taking nelfinavir-based regimens. The utility of therapeutic drug monitoring (TDM) has previously been reported in the ATHENA study, a trial in which the use of TDM as a part of clinical care provided a better virological outcome as well as fewer treatment discontinuations as a result of toxicity. When integrating the information of TDM with that of HIV genotyping, drug regimens might be modified in a more rational fashion.
AIDS 2003; 17(3):442-444
Daniel Gonzalez de Requenaa; Marina Nunezb; Carmen de Mendozab; Inmaculada Jimenez-Nachera; Vincent Sorianob
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