Clinical Management of Resistance AMJ Wensing, MD, PhD
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
n case of failure AND sufficient therapy adherence Resistance may be selected and detected How do you manage this as a clinician?
Most relevant NRT resistance mutations
Most relevant NNRT and integrase resistance mutations MUTATONS N THE REVERSE TRANSCRPTASE GENE ASSOCATED WTH RESSTANCE TO NON-NUCLEOSDE NUCLEOSDE NHBTORS
Most relevant Protease resistance mutations
www. ASUSA.ORG: pocketcard
Outcome after virological failure improved by resistance testing and use of interpretation tools Havanna Trial, Tural et al ADS 2002.
Webbased algorithms for interpretation of resistance profiles www.hivdb.stanford.edu www.hiv-grade.de www.hivfrenchresistance.org
Case 64 year old male is treated with nevirapine zidovudine and lamivudine Doing clinically well ssues with adherence Rebound VL log 124.000 copies/ml Resistance test is performed
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
Based on the algorithms a switch to dolutegravir (integrase inhibitor) abacavir and lamivudine available as a single tablet regimen in the NL was made
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: http://defiant.corban.edu/gtipton/net-fun/iceberg.html
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
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
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
Switch from boosted P to raltegravir in subjects with treatment history HV-1 RNA < 50 c/ml (%) 100 90 80 70 60 50 0 4 Protocol 032 Protocol 033 : -6.6 (95% C: -14.4 to 1.2) 87% 81% 8 12 24 Weeks RAL + ARVs, N 174 166 169 173 172 176 176 176 176 175 LPV/RTV + ARVs, N 174 171 171 171 174 178 178 177 177 178 HV-1 RNA < 50 c/ml (%) 100 90 80 70 60 50 : -5.8 (95% C: -12.2 to 0.2) 0 4 94% 88% 8 12 24 Weeks Predefined criteria for noninferiority: lower limit of the 95% C for treatment difference > -12%; NC = F analysis Eron J, et al. Lancet 2010
Back to our patient with a severely compromised backbone he started virtual dolutegravir monotherapy at a viral load of 230.000
What would you do? A (red) Continue Therapy B (blue) Adapt Therapy
Frequent failure with maintenance DTG-monotherapy J. Blanco et al. CRO 2027
What would you do? A (red) Continue Therapy B (blue) Adapt Therapy Darunavir was added to his regimen
Case 2 Female 41 jaar Flower decorator Tested for HV when she heard her former partner was positive Baseline: CD4: 158 cells, VL 900.000 kp Start Efavirenz, TDF and FTC
nitial Rapid decrease of Viral load
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
What would you do? - A (red) Restart the same ART - B (blue) Start with another ART combination - C (yellow) Resistance test
No resistance related mutations detected 15-10-2014 GRADE / HVDB Stanford
No resistance found What would you do? - A (red) Restart the same ART - B (blue) Start with another ART combination
Continuation of current regimen: Viral load decreases
Continuation of current regimen: Viral rebound
15-01-2017 GRADE / HVDB Stanford
103N 103N 103N + 65R
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
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!
Met Dank aan. Translationele Virologie Research Groep UMCU
Hypergevoeligheid zidovudine na ontwikkeling van resistentie tegen tenofovir