Clinical Management of Resistance. AMJ Wensing, MD, PhD

Transcription

1 Clinical Management of Resistance AMJ Wensing, MD, PhD

2 Changing treatment paradigm First Line Second Line? New First Line North America Western Europe: Eastern Europe Africa mix South America mix More possibilities More complex Possibility to make a wrong choice

3 n case of failure AND sufficient therapy adherence Resistance may be selected and detected How do you manage this as a clinician?

4 Most relevant NRT resistance mutations

5 Most relevant NNRT and integrase resistance mutations MUTATONS N THE REVERSE TRANSCRPTASE GENE ASSOCATED WTH RESSTANCE TO NON-NUCLEOSDE NUCLEOSDE NHBTORS

6 Most relevant Protease resistance mutations

7 www. ASUSA.ORG: pocketcard

8 Outcome after virological failure improved by resistance testing and use of interpretation tools Havanna Trial, Tural et al ADS 2002.

9 Webbased algorithms for interpretation of resistance profiles

10 Case 64 year old male is treated with nevirapine zidovudine and lamivudine Doing clinically well ssues with adherence Rebound VL log copies/ml Resistance test is performed

11 nterpretation according to 3 webbased algorithms Specific resistance related mutations 3TC/FTC ABC AZT TDF A B C S S S S R S S RT: EFV ETR R R 41L, 215Y NVP RPV R R R R 181C Boosted Ps S S S Ns S S S

12 Based on the algorithms a switch to dolutegravir (integrase inhibitor) abacavir and lamivudine available as a single tablet regimen in the NL was made

13 Virological failure on a lamivudine containing regimen 184V? Lamivudine/emtricitabine resistance is easily selected if there is active viral replication during ART Can be used as an indicator whether the drug is still being used f adherence drops it is easily replaced by wildtype in the active replicating population However it is preserved in the proviral DNA archive and will be easily reselected ceberg adopted from:

14 nterpretation according to 3 webbased algorithms A B C Specific mutaties 3TC/FTC ABC AZT R R R R R RT: TDF S SL 41L, 215Y EFV ETR R R + 184V NVP RPV R R R R +181C Boosted Ps S S S Ns S S S

15 What can we learn from this A single mutant may lead to resistance to one particular drug For resistance to other drugs several mutations are needed Algorithms give advise on the susceptibility of individual drug resistance mutations detected in the plasma Algorithms do not take into account archived resistance Algorithms do not advise on combination therapy Patient s story and therapy history are required as input

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17 mportance of therapy History HV infected individuals with a history of therapy failure Well suppressed on a boosted P (high genetic barrier drug) containing regimen Randomised to continue the use of a boosted P (lpv/r) or to replace the P to raltegravir (low genetic barrier drug) Eron J, et al. Lancet 2010

18 Switch from boosted P to raltegravir in subjects with treatment history HV-1 RNA < 50 c/ml (%) Protocol 032 Protocol 033 : -6.6 (95% C: to 1.2) 87% 81% Weeks RAL + ARVs, N LPV/RTV + ARVs, N HV-1 RNA < 50 c/ml (%) : -5.8 (95% C: to 0.2) % 88% Weeks Predefined criteria for noninferiority: lower limit of the 95% C for treatment difference > -12%; NC = F analysis Eron J, et al. Lancet 2010

19 Back to our patient with a severely compromised backbone he started virtual dolutegravir monotherapy at a viral load of

20 What would you do? A (red) Continue Therapy B (blue) Adapt Therapy

21 Frequent failure with maintenance DTG-monotherapy J. Blanco et al. CRO 2027

22 What would you do? A (red) Continue Therapy B (blue) Adapt Therapy Darunavir was added to his regimen

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24 Case 2 Female 41 jaar Flower decorator Tested for HV when she heard her former partner was positive Baseline: CD4: 158 cells, VL kp Start Efavirenz, TDF and FTC

25 nitial Rapid decrease of Viral load

26 Rapid decrease in viral load but than. She had an important flowershow that took all her time and attention She concluded it was better to stop ART than taking the drugs irregurlarly

27 What would you do? - A (red) Restart the same ART - B (blue) Start with another ART combination - C (yellow) Resistance test

28 No resistance related mutations detected GRADE / HVDB Stanford

29 No resistance found What would you do? - A (red) Restart the same ART - B (blue) Start with another ART combination

30 Continuation of current regimen: Viral load decreases

31 Continuation of current regimen: Viral rebound

32 GRADE / HVDB Stanford

33 103N 103N 103N + 65R

34 What can we learn from this case Selection of resistance can take place while being off therapy Half life of drugs may be different f a NRT/NNRT regimen is interrupted a NNRT tail of monotherapy may arise selecting for resistance NNRT mutations are known to stick around without treatment pressure, but that is in therapy naïve patients, without wildtype virus f wildtype is present, wild type may take over as drug levels disappear

35 Conclusion Resistance testing is an extra tool, but looking at patients story and history is as important when in clinical management of cases with resistant virus Use the algorithms, consult the experts!

36 Met Dank aan. Translationele Virologie Research Groep UMCU

37 Hypergevoeligheid zidovudine na ontwikkeling van resistentie tegen tenofovir