Salvage Antiretroviral Therapy

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

2. HIV: Case History • A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm3 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? DHS/ HIV/PP

3. 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? DHS/ HIV/PP

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

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

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

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 Pre-treatment: wild-type On Treatment: resistance Poor Adherence Wild-type HIV Resistant HIV

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

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

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

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

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

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 TestingVirtual Phenotype Genotype Access Data HIV RT Protease 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