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Higher efavirenz concentrations determine the response to viruses carrying non-nucleoside reverse transcriptase resistance mutations: TDM
  AIDS: Volume 18(15) 21 October 2004
González de Requena, Daniela; Gallego, Oscarb; Corral, Angélicab; Jiménez-Nácher, Inmaculadaa; Soriano, Vincentb
aPharmacology Unit and bService of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Sponsorship: This work was partly supported by grants from Asociacion Investigacion y Educacion en SIDA, Comunidad Autonoma de Madrid and Red de Investigaciones Sanitarias.
We examined the influence of both efavirenz plasma concentrations and non-nucleoside reverse transcriptase (NNRTI) resistance mutations on the antiviral activity of efavirenz in patients experiencing early virological failure under nevirapine-containing regimens. Up to 41% of patients reach less than 50 copies/ml at 48 weeks. No association was found between the presence of NNRTI resistance mutations and virological outcome. Nevertheless, patients responding virologically and carrying NNRTI-resistant viruses had higher efavirenz levels than those who did not respond.
Non-nucleoside reverse transcriptase inhibitors (NNRTI) show high antiviral activity against HIV-1 infection, and indirect evidence suggests that efavirenz is particularly potent. Nevertheless, the development of single mutations at critical sites within the reverse transcriptase gene can reduce or even annul NNRTI activity. It is generally believed that broad cross-resistance between NNRTI is the main factor limiting their sequential use. This is particularly true in patients failing for long periods of time on NNRTI-based regimens, when the accumulation of multiple mutations occurs. Nevertheless, both in-vitro and in-vivo studies have suggested that efavirenz could be effective against HIV-1 strains carrying some NNRTI resistance mutations. On the other hand, efavirenz plasma concentrations have been shown to influence the virological response to NNRTI-based regimens.
The aim of this study was to determine whether the use of efavirenz in patients showing early virological failure under a nevirapine-based regimen may allow them to regain complete viral suppression. The role of both efavirenz plasma levels and NNRTI resistance mutations in the effectiveness of this intervention was also analysed.
For this purpose, 48 patients who showed plasma viral load rebound over 50 HIV-RNA copies/ml (confirmed in two separate specimens collected 2 weeks apart) after being undetectable for at least 3 months under a nevirapine-based triple combination (nevirapine, 200 mg twice a day) were selected. Nevirapine was substituted by efavirenz (600 mg a day) keeping the same two nucleoside reverse transcriptase inhibitors (NRTI) as backbone.
The plasma HIV-RNA level was determined using the third-generation branched DNA assay. Measurements were performed at baseline, 3, 6 and 12 months after replacing nevirapine by efavirenz. A significant virological response was defined when the plasma viral load reduction was over 1 log or reached less than 50 HIV-RNA copies/ml.
Nevirapine plasma concentrations were determined before the morning dose intake (Ctrough) using a validated high-performance liquid chromatography method with ultraviolet detection. Efavirenz plasma concentrations were determined at a median time of 12 h after the night dose intake using the same high-performance liquid chromatography method as for nevirapine.
HIV-1 reverse transcriptase genetic sequences were obtained at baseline using an automatic sequencer (ABI 3000; Applied Biosystems, Foster city, CA, USA). Drug resistance genotypic interpretation was performed according to the latest International AIDS Society USA resistance guidelines ( www.iasusa.org ) and expert advice. Resistance to efavirenz was considered in the presence of either K103N or Y188L, or when two or more other NNRTI resistance mutations were present. Resistance to nevirapine was considered in the presence of any NNRTI resistance mutation recorded in the International AIDS Society USA list.
Statistical analyses were performed using SPSS version 9.0 (SPSS Inc., Chicago, IL, USA), using either parametric or non-parametric tests as needed. Significance was considered for P values below 0.05.
At the time of first virological failure on nevirapine, patients had been exposed to the drug for a median (range) time of 7.4 months. The median (range) plasma viral load was 4313 (72-45 148) HIV-RNA copies/ml. A total of 29 of 35 subjects (83%) for whom genetic material could be amplified and sequenced harboured one or more NNRTI resistance mutations. The median (interquartile range; IQR) nevirapine Ctrough at the time of viral rebound was 3.6 μg/ml (2.4-4). Interestingly, patients lacking NNRTI resistance mutations (six out of 35) at the time of viral rebound had lower nevirapine Ctrough [median (IQR) 3.4 μg/ml (2.05-4.05) versus 0.03 μg/ml (0-3.4)], although this difference did not reach statistical significance (P = 0.058).
Table. Plasma viral load changes (delta log plasma viral load) and EFV plasma concentration at weeks 12, 24 & 48. (Cpl=plasma concentrations; ug/ml)
Week 12
Log VL EFV Cpl
Total -0.4 3.5
Viral responders -1.3 4.7
Nonresponders 0.1 2.4
p-value 0.1

Week 24
Log VL EFV Cpl
Total -0.64 3.8
Viral responders -1.25 4.6
Nonresponders -0.1 2.6
p-value 0.04

Week 48
Log VL EFV Cpl
Total -0.56 2.7
Viral responders -1.2 3.4
Nonresponders -0.3 1.76
p-value 0.06

After replacing nevirapine by efavirenz, a significant virological response was recorded in 20 (41.7%), 23 (48%) and 20 (41.7%) patients at weeks 12, 24 and 48, respectively (intent-to-treat analysis). An undetectable plasma viral load (< 50 copies/ml) was reached in 25, 39.6 and 41.7% of subjects at weeks 12, 24 and 48, respectively.
It should be pointed out that in our study there were no discontinuations of therapy as a result of efavirenz-related adverse effects, although two individuals complained of dizziness and one of vivid dreams plus insomnia. Nevertheless, symptoms tended to solve spontaneously after the first weeks on therapy.
When efavirenz-associated resistance mutations were considered, no association between their presence and the virological response was found at any timepoint. In contrast, efavirenz plasma concentrations were higher in virological responders at any timepoint with respect to non-responders (see Table 1). Moreover, patients who attained a significant virological response at week 12 despite carrying efavirenz-associated resistant strains had significantly higher efavirenz plasma concentrations than those who did not respond [median (IQR) 3.6 μg/ml (2.8-6.4) versus 2.7 μg/ml (1.4-2.9); P = 0.027, respectively].
A positive significant correlation was found at week 12 between efavirenz plasma concentrations and Δlog plasma viral load (r = -0.4; P = 0.007). This significant correlation was still present at week 48, although in to a lesser extent (r = -0.41; P = 0.03).
At week 12, 75% of patients carrying viruses with efavirenz-associated resistance mutation strains and efavirenz plasma levels greater than 3 μg/ml showed a significant virological response. In contrast, it occurred in only 22% of patients showing efavirenz plasma levels of less than 3 μg/ml. This critical threshold for efavirenz plasma concentrations associated with the chance of attaining a significant virological response was also confirmed at weeks 24 and 48 (79 versus 40%; P = 0.03; and 76.4 versus 41.6%; P = 0.03; respectively).
Our results demonstrate that complete and sustained viral suppression lasting up to 48 weeks is feasible in up to 41% of patients who showed early virological failure under a nevirapine-based regimen. This benefit of taking efavirenz was independent of the presence of NNRTI resistance mutations. Nevertheless, the initial response to this intervention was mainly driven by efavirenz plasma concentrations. The attainment of adequate efavirenz plasma levels (> 3 μg/ml) in the early stages of the intervention was associated with the chances of virological success. Hypothetically, high efavirenz plasma concentrations could overcome resistance in a relatively large proportion of patients failing nevirapine.
On the other hand, virological failure to nevirapine-based regimens was almost always caused by the selection of NNRTI resistance mutations. Only 17% of patients lacked resistance mutations at the time of failure, and as expected most of these individuals were not ot compliant and showed low or undetectable nevirapine plasma trough levels.
In summary, therapeutic drug monitoring of nevirapine plasma concentrations at the time of the first viral rebound could help to identify those patients who may benefit from interventions focused on improving drug adherence or alternatively to attempt a rescue intervention based on efavirenz. In the latest situation, therapeutic drug monitoring of efavirenz plasma concentrations could help to optimize the efavirenz dose in an attempt to overcome resistance.
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