1. Track B Workshop Controversies in the Management of HIV-positive Adults: A Case-Based Approach Sasisopin Kiertiburanakul, MD, MHS Associate Professor Department of Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University 7 th IAS, Kuala Lumpur (July 1, 2013)

2. HIV Drug Resistance and Treatment Failure

3. Case  41-year-old policeman  No known underlying disease  May 08: weight lost, anti-HIV positive  No history of opportunistic infections  CD4 count 35 cells/mm 3  HBsAg: negative  Married for 10 years  No condom use  Going to start ART

4. HIV Drug Resistance Testing before ART  A. Yes  B. No

5. His Wife  Diagnosed of HIV infection, PCP, pulmonary TB, cryptococcal meningitis and CMVR in 2004 Nadir CD4 count 57 cells/mm 3  First regimen in 2005: d4T/3TC/NVP  May 07: CD4 count 106 cells/mm 3, HIV VL 27,100 copies/mL V75I, K101E, M184V, G190A  Change to AZT + ddI + LPV/r  April 08: CD4 count 144 cells/mm 3, HIV VL 19,500 copies/mL I13V, K20R, M36I, H69K, L89M

6. HIV Drug Resistance Testing before ART  A. Yes  B. No

7. Primary HIVDR in Your Setting/Country?  A. <1%  B. 1-5%  C. 6-10%  D. >10%  E. No idea!!!

8. Primary HIVDR in Asia  ART-naïve patients enrolled in the TREAT Asia Studies to Evaluate Resistance, 2007-2010  11 sites, 5 countries Duration of HIV infection No. of patients (n) No. of patients with drug resistance (n) Prevalence of drug resistance (%) p-value* Recent458286.110.065 Chronic1,340544.03 Total1,798824.56 Kiertiburanakul S, et al. Plos One 2013 (in press)

9. HIV Drug Resistance Testing Recommendation SettingsIAS-USA 1 DHHS 2 European 3 Thai 4 WHO 5 Primary/acute Recommend — — Post-exposure prophylaxis ——Recommend*— — Chronic and treatment naïve Recommend — — Failure Recommend — Pregnancy Recommend — — 1. Thompson MA, et al. JAMA 2012;308:387-402. 2. DHHS Guideline, February 2013. Available at: http://www.aidsinfo.nih.gov. 3. Vandamme A, et al. AIDS Rev 2011;13:77-108. EACS Guideline, November 2012. Available at: http://www.europeanaidsclinicalsociety.org. 4. Bureau of AIDS, TB, and STIs and Thai AIDS Society (TAS). Asian Biomed 2010;4:515-28. 5. 2010 WHO Guideline. *Especially if exposure to someone receiving antiretroviral drugs is likely or if prevalence of drug resistance in untreated patients ≥5% (European: ≥10%).

10. Resistance-associated RT Mutations: No relevant mutations detected Nucleoside and Nucleotide RT InhibitorsResistance Interpretation abacavir (ABC)No Evidence of Resistance didanosine (ddI)No Evidence of Resistance lamivudine (3TC)/emtricitabine (FTC)No Evidence of Resistance stavudine (d4T)No Evidence of Resistance tenofovir (TDF)No Evidence of Resistance zidovudine (AZT)No Evidence of Resistance Non-nucleoside RT InhibitorsResistance Interpretation efavirenz (EFV)No Evidence of Resistance nevirapine (NVP)No Evidence of Resistance amprenavir (APV)/fosamprenavir (FPV) No Evidence of Resistance APV/r or FPV/r Resistance atazanavir (ATV) Possible Resistance ATV/r No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance indinavir (IDV) No Evidence of Resistance IDV/r No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance nelfinavir (NFV) No Evidence of Resistance saquinavir + ritonavir (SQV/r) Resistance tipranavir + ritonavir (TPV/r) Possible Resistance Resistance-associated PR Mutations: L10I/V, I13V, I15V, G16E, K20I, M36I, H69K, L89M Protease InhibitorsResistance Interpretation HIV Genotype before ART

11. First ARV Regimen for Him?  A. TDF + 3TC/FTC + EFV  B. TDF + 3TC/FTC + LPV/r  C. TDF + ABC + LPV/r  D. TDF + AZT + DRV/r  E. ETR + DRV/r + RAL His wife HIV resistance mutations May 07: V75I, K101E, M184V, G190A April 08: I13V, K20R, M36I, H69K, L89M d4T/3TC/NVP  AZT + ddI + LPV/r with detectable HIV VL Baseline HIV VL 29,655 copies/mL

12. Case  May 08: TDF + 3TC + NVP  Sep 08: CD4 count 75 cells/mm 3, HIV VL 2,909 copies/mL  Genotypic resistance testing II

13. Resistance-associated RT Mutations: K65R, K101E, G190S Nucleoside and Nucleotide RT InhibitorsResistance Interpretation abacavir (ABC) Possible Resistance didanosine (ddI) Possible Resistance lamivudine (3TC)/emtricitabine (FTC) Possible Resistance stavudine (d4T) No evidence of Resistance tenofovir (TDF) Resistance zidovudine (AZT) No evidence of Resistance Non-nucleoside RT InhibitorsResistance Interpretation efavirenz (EFV)Resistance nevirapine (NVP)Resistance atazanavir (ATV) No Evidence of Resistance ATV/r No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance fosamprenavir (FPV) No Evidence of Resistance FPV/r No Evidence of Resistance indinavir (IDV) No Evidence of Resistance IDV/r No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance nelfinavir (NFV) No Evidence of Resistance saquinavir + ritonavir (SQV/r) Possible Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance Resistance-associated PR Mutations: I13V, I15V, G16E, K20I, M36I, H69K, L89M Protease InhibitorsResistance Interpretation

14. What Is The Next Regimen (Backbone)? Resistance-associated RT Mutations: K65R, K101E, G190S Nucleoside and Nucleotide RT InhibitorsResistance Interpretation abacavir (ABC) Possible Resistance didanosine (ddI) Possible Resistance lamivudine (3TC)/emtricitabine (FTC) Possible Resistance stavudine (d4T) No evidence of Resistance tenofovir (TDF) Resistance zidovudine (AZT) No evidence of Resistance Non-nucleoside RT InhibitorsResistance Interpretation efavirenz (EFV)Resistance nevirapine (NVP)Resistance A.AZT + TDF D. AZT only B.AZT + 3TCE. No NRTIs C.AZT + ABC Current regimen: TDF + 3TC + NVP

15. What Is The Next Regimen (Others)? A.Boosted PI B.Boosted PI + ETR C.Boosted PI + RAL D.Boosted PI + RAL + ETR E.MVC + RAL + ETR Resistance-associated RT Mutations: K65R, K101E, G190S Nucleoside and Nucleotide RT InhibitorsResistance Interpretation abacavir (ABC) Possible Resistance didanosine (ddI) Possible Resistance lamivudine (3TC)/emtricitabine (FTC) Possible Resistance stavudine (d4T) No evidence of Resistance tenofovir (TDF) Resistance zidovudine (AZT) No evidence of Resistance Non-nucleoside RT InhibitorsResistance Interpretation efavirenz (EFV)Resistance nevirapine (NVP)Resistance ETR score = 2.5 (intermediate response)

16. Case  May 08: TDF + 3TC + NVP  Sep 08: CD4 count 75 (4%) cells/mm 3, HIV VL 2,909 copies/mL  Genotypic resistance testing II  Oct 08: change to AZT/3TC, LPV/r  Feb 09, Jun 09: HIV VL <40 copies/mL  Dec 10: CD4 count 261 (15%) cells/mm 3, HIV VL <40 copies/mL

17. Case  Sep 11: CD4 count 291 cells/mm 3, HIV VL <40 copies/mL  Lipodystrophy: change to TDF/FTC, LPV/r  Nov 11: CD4 count 370 cells/mm 3, HIV VL <40 copies/mL  Nov 12: CD4 count 372 cells/mm 3, HIV VL <20 copies/mL  June 13: CD4 count 389 cells/mm 3, HIV VL <20 copies/mL

18. The HIV Second-line Therapy AntiRetroviral study in patients who failed NNRTI-based regimens VariableTotal (N =195) Age, years37.5 (6.9) Male, %58 Weight, kg58.3 (10.7) CDC clinical classification A:B:C, %23:22:55 Baseline CD4 count, cells/mm 3 204 (135) Baseline HIV-RNA, log 10 copies/mL4.1 (0.6) Genotypic resistance for NRTI, % M184V/I82 K65R7 Multi NRTI resistance*18 * Multi-NRTI mutations were defined as having ≥4 thymidine analog mutations (TAMs) or Q151M complex or 69 insertion Bunupuradah T, et al. Antivir Ther 2012;17:1351-61.

19. 0 10 20 30 40 50 60 70 80 90 100 Mono-LPV/r-armTDF/3TC/LPV/r-arm HIV-RNA ≥400 copies/mL HIV-RNA <400 copies/mL HIV-RNA <200 copies/mL HIV-RNA <50 copies/mL % Virological suppression HIV-RNA (copies/mL) Mono-LPV/r (%)TDF/3TC/LPV/r (%)P-value <40075860.053 <20069860.01 <506183<0.01 Bunupuradah T, et al. Antivir Ther 2012;17:1351-61.

20. Take Home Message  Routine HIVDR testing prior to ART initiation may become consideration Local prevalence of primary HIVDR Possibility to acquire HIV drug resistance  Limited options of the 2 nd line regimen in a resource limited setting