1. Salvage Antiretroviral Therapy Guiding Principles, Strategies and the Role of Resistance Testing

2. DHS/ HIV/PP HIV: Case History  A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm 3 is started on a regimen of AZT (zidovudine) plus 3TC (lamivudine) plus Nevirapine. He has an initial excellent response: HIV viral load < 50 at months 3, 6, and 9, and his CD4 count rises to 247. At the 12 month visit, he admits to missing some doses in the past month.  What would you do?  Would you change his regimen?

3. DHS/ HIV/PP HIV: Case History  You re-address his adherence problems  You continue his current regimen but order a viral load and CD4 count.  His 12 month HIV RNA level comes back at 224 copies/mL; CD4 count is essentially unchanged.  What would you do?

4. DHS/ARV Rx/PP HIV Case continued Medications Started 50

5. HIV Case continued The viral load is repeated 2 weeks later and returns at 822 copies/ml.

6. DHS/ARV Rx/PP HIV Case continued Medications Started 50

7. HIV Case continued The viral load is repeated 2 weeks later and returns at 822 copies/ml. Would you change his regimen? Would you order a resistance test?

8. Antiretroviral Resistance Testing due to HIV’s high transcription error rate and high level of replication, mutant HIV variants constantly generated these variants often contain mutations that confer variable levels of resistance to antiretroviral agents poor adherence or suboptimal regimens can lead to resistance and ‘viral breakthrough’

9. HIV Case continued Wild-type HIV Resistant HIV Pre-treatment: wild-type On Treatment: resistance Poor Adherence

10. Antiretroviral Resistance Testing Goal of resistance testing is to identify these resistance-conferring mutations in order to more intelligently design a ‘salvage’ regimen Studies have documented clinical benefit of resistance testing Expert advice on interpretation of the genotype carries a similar and additive benefit as well

11. Summary of Randomized Controlled Trials of Resistance Testing

12. Antiretroviral Resistance Testing: Guidelines for Implementation

13. DHS/ARV Rx/PP Antiretroviral Therapy: Viral Failure Medications Started 50

14. DHS/ARV Rx/PP Antiretroviral Therapy: Failure to Suppress Medications Started 50

15. DHS/HIV/Resistance /PP HIV Primary Infection Isolates From: Little SJ. JAMA 1999;282:1142-9. Little SJ. 8th Conf Retrovirus. Abstract 756 N = 108 Patients Newly HIV-Infected Phenotypic Data: 10-fold Resistance

16. Resistance Testing: Acute vs. Chronic HIV Infection Wild-type HIV Resistant HIV Acute HIV Chronic HIV No Therapy

17. Resistance Testing: On (Failing) Therapy vs Off Therapy Wild-type HIV Resistant HIV On Therapy Off Therapy ARV Rx stopped

18. Resistance Testing: Genotypic Assays  Reports mutations in Reverse Transcriptase & Protease genes  Generally require > 1,000 copies/mL  Turn-around time of approximately two weeks  cost: around $400  several trials have demonstrated clinical benefit

19. Resistance Testing: Phenotypic Assays  Determine amount of drug required to suppress HIV replication in vitro  intuitively simpler but less clinical experience, less data demonstrating benefit  Generally require > 1,000 copies/mL  turn-around time of approximately four weeks  cost: close to $1,000

20. Genotyping vs Phenotyping discordance common between the two assays genotypic assays suffer from complexity of interpretation, potentially unknown interactions between various mutations phenotypic assays suffer from lack of consensus on susceptibility cut-offs for most agents, inability to delineate mutation patterns underlying resistance, high cost, and lengthy turn-around time

21. HIV Resistance Testing Virtual Phenotype Genotype Proteas e RTHIV Access Data Genotype & Phenotype Data Virtual Phenotype Wild-type HIV Resistant HIV

22. HIV Case continued You obtain a genotype which shows the K103N mutation in the Reverse Transcriptase Gene Would you change the nevirapine in his regimen to efavirenz?

23. Salvage Antiretroviral Therapy: Guiding Principles Always confirm viral failure with repeat viral load measurements Re-visit adherence issues Try to correct adherence problems before starting a salvage regimen

24. Salvage Antiretroviral Therapy: Guiding Principles for adherence or intolerance problems, can change single agent in the regimen as long as resistance is not suspected for cases of viral failure or failure to achieve sustained virologic suppression, must change at least two of the agents; an entirely new regimen is best though not always feasible beware of cross-resistance within a class

25. Salvage Antiretroviral Therapy: Guiding Principles trials have demonstrated the clinical benefit of resistance testing in designing salvage regimens, but resistance testing can miss minor resistant variants of HIV trials have also demonstrated the clinical benefit of expert assistance in designing salvage regimens

26. Salvage Antiretroviral Therapy: Guiding Principles Many patients have limited salvage options; it is sometimes rational to continue a ‘failing’ regimen in order to maintain partial viral suppression discontinuation of HAART should be considered for patients experiencing return to viral baseline and declining CD4 count who do not have rational salvage options

27. Salvage Regimens & Resistance Testing: Key Points Consider salvage regimens for virologic failure, failure to suppress, immune deterioration, or inadherence/toxicity resistance testing is indicated for virologic failure, failure to suppress, and acute HIV infection expert advice has proven clinical benefit in interpreting resistance tests and designing salvage regimens