 |
|
|
| |
Tenofovir in salvage therapy: K65R, TAMS, Kaletra
|
| |
| |
"Development of resistance mutations in patients receiving salvage therapy with tenofovir"
Reported by Jules Levin
ABSTRACT 154
Antiviral Therapy 2004; 9:S170.
J Grebely, J Raffa and B Conway
University of British Columbia, Canada
This was a retrospective chart review to examine the efficacy of Tenofovir, the predictors of viral failure for these patients on tenofovir therapy, and to determine the correlates of development of the K65R tenofovir-associated drug mutation.
AUTHOR CONCLUSION:
1. Overall, the use of TDF in treatment-experienced patients was associated with virologic suppression in 53% of cases (68 patients evaluated).
2. by univariate analysis, the predictors of virologuc failure were baseline CD4 count <200 and the use of triple or dual NRTI-therapy. Concomitant use of lopinavir/ritonavir (Kaletra) with TDF was a significant predictor of virologic suppression.
3. the emergence of K65R was observed in 12% of the overall study population (6% in patients on double/triple class HAART vs 33% in patients on triple or dual NRTI therapy), consistent with data reported in drug-naïve populations.
4. the predictors of the emergence of K65R were dual or triple NRTI-therapy and the presence of any TAMS at baseline (0.06). Concomitant use of Kaletra with TDF was a significant predictor of non-emergence of K65R.
5. both patients having K65R at baseline have maintained viral suppression over a median of 27 weeks of followup on Kaletra based therapy.
6. the presence of TAMS at baseline do not predict viral failure but do predict the lack of emergence of K65R. This is consistent with other studies showing K65R and TAMS display bi-directional phenotypic antagonism.
7. it is noteworthy that 0/16 patients with TAMS at baseline developed K65R, although this did not affect the likelihood of virologic suppression (8/16; 50% vs 36/68 in the overall group).
8. TDF based HAART remains quite effective in treatment-experienced patients especially if combined with Kaletra. The identification of specific baseline parameters (such as specific patterns of pre-existing TAMS) may help identify a sub-population that will most benefit from TDF-based HAART. The evaluation of this hypothesis requires a larger sample size than is available to us in our single center.
BACKGROUND: Tenofovir (TDF) is often used in salvage therapy due to its activity against many NRTI-resistant strains and a low initial prevalence of the K65R mutation (about 3%). High rates of viral failure have been observed in treatment-naïve patients receiving TDF in combination with non-thymidine NRTIs in the setting of triple-NRTI HAART. Early viral failure in drug naïve patients receiving triple-NRTI HAARTtherapy isassociated with an increased emergence of K65R. There are only limited data on 12 patients regarding the emergence of K65R in treatment-experienced patients receiving TDF. Concurrent use of thymidine analogues with TDF may reduce the rate of K65Remergence, but other factors may also be important. This led us to hypothesize that certain pre-existing mutations in RT may have a clinical relevance in the prevention or reduction of the emergence of the K65R mutation. With this in mind, we evaluated the evolution of genotypic NRTI resistance in treatment-experienced patients receiving TDF.
The objectives are to evaluate the virologic efficacy and predictors of failure of TDF-based HAART in treatment-experienced patients. And to define the correlates of emergence of the K65R mutation in this population.
All patients receiving TDF-based therapy >3 months were included in this retrospective chart review. Study endpoints were virological suppression <400 copies/ml and the evolution of drug resistance mutations in thesetting of virological failure.
For the purpose of this analysis, patients who were suppressed at followup were assumed to carry wild-type isolates with respect to the K65R mutation. Baseline genotype was performed on 47 patients.
RESULTS: A total of 68 patients (57 men, 11 women) were evaluated, including 15 males on a triple/dual NRTI regimen. Baseline CD4 and plasma viral load in the latter group (230 cells/mm3 and 21,800 copies/ml) compared to values of 200 cells/mm3 and 87,100 copies/ml in the patients on double class regimens. At a median 52 weeks, similar increases in CD4 count were observed (+42 and +25 cells/mm3) and median plasma viral load was 102 and 2850 copies/ml in patients on double and single class regimens, respectively. Maximal virological suppression (intent-to-treat; <400 copies/ml) was achieved in 31/50 (62%) and 3/15 (20%) patients receiving double and single class regimens.
The emergence of K65R (n=8) was more frequent on triple-NRTI regimens (33%, n=5) than standard HAART (6%, n=3). Other RT mutations were always present.
GENOTYPE AT BASELINE
|
|
Total n=47(%)
|
Success
|
Failure
|
OR
|
p-value
|
|
NNRTI
|
|
--K103N
|
13(28)
|
5
|
8
|
0.63
|
0.53
|
|
--Y181C/I
|
12(26)
|
8
|
4
|
3.00
|
0.18
|
|
PI
|
30(64)
|
14
|
16
|
3.40
|
0.26
|
|
M184V
|
25(53)
|
11
|
14
|
0.79
|
NS
|
|
TAMS
|
|
--M41L
|
11(23)
|
6
|
5
|
1.51
|
NS
|
|
--D67N
|
7(15)
|
4
|
3
|
1.63
|
NS
|
|
--K70R
|
2(4)
|
1
|
1
|
1.15
|
NS
|
|
--L210W
|
6(13)
|
3
|
3
|
1.16
|
NS
|
|
--T215Y/F
|
10(21)
|
5
|
5
|
1.18
|
NS
|
|
--K219Q/E/N/R
|
7(15)
|
3
|
4
|
0.84
|
NS
|
|
Other NRTI Mutations
|
|
--E44D
|
3(6)
|
2
|
1
|
2.37
|
NS
|
|
V118I
|
4(9)
|
2
|
2
|
1.15
|
NS
|
Of note, one patient received TDF-ABC alone over 16 months, maintained a viral load 3,000--15,000 copies/ml without the development of the K65R mutation. This patient started 3TC/d4T/IDV with good CD4 increase & viral load decline. Baseline was 100,000 c/ml & Cd4 of about 300. Cd4 count was mostly between 500-700 throughout this entire period except for 1 excursion to 250. Patient switched to 3TC/d4T and maintained low viral load & good cd4 count. After 3 years on 3TC/d4T, genotype showed 67N/70R/184V/219Q and was switched to ABC/d4T. Low viral load remained sustained. Patient then switched to ABC/TDF (67N/70R). CD4 maintained at 500 & VL remained low.
PREDICTORS OF VIRAL FAILURE
|
|
N
|
Success
|
Failure
|
OR
|
p-value
|
|
Baseline VL>100*(000
|
29
|
12
|
17
|
2.34
|
0.14
|
|
Baseline CD4<200
|
34
|
13
|
21
|
3.30
|
0.03
|
|
Triple/dual NRTI
|
15
|
3
|
12
|
6.40
|
0.007
|
|
Current use of LPV/r
|
21
|
16
|
5
|
0.24
|
0.02
|
|
Current use of thymidine analogue
|
6
|
2
|
4
|
0.42
|
NS
|
|
Current ABC/ddI/3TC
|
63
|
34
|
29
|
1.74
|
NS
|
|
Exposure to non-HAART
|
37
|
20
|
17
|
1.10
|
NS
|
PREDICTORS OF EMERGENCE OF THE K65R MUTATION
|
|
N
|
K65R
|
No K65R
|
OR
|
p-value
|
|
|
|
N=6
|
|
|
|
|
Basl vl>100*(000 c/ml
|
29
|
5
|
24
|
2.50
|
0.27
|
|
Basl cd4<200
|
34
|
5
|
29
|
1.77
|
NS
|
|
Triple/dual NRTI
|
15
|
5
|
10
|
7.97
|
0.01
|
|
Current LPV/r
|
21
|
0
|
21
|
0
|
0.051
|
|
Current thym ana
|
6
|
2
|
4
|
4.5
|
0.14
|
|
Current ABC/ddI/3TC
|
63
|
7
|
56
|
0.51
|
NS
|
|
Exposure to pre-HAART
|
37
|
5
|
32
|
1.45
|
NS
|
CONCLUSIONS: Virological response to TDF in salvage therapy was poorer in patients on single class regimens, and was associated with the development ofK65R. TAMS (AZT-like mutations) may protect against its development and may help identify a subgroup of patients in whom TDF resistance may be slower to develop after its initiation in salvage therapy.
|
| |
|
|
|
|
|
