HIV Drug Resistance and How to Manage HAART failure

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1 HIV Drug Resistance and How to Manage HAART failure Kiat Ruxrungtham Professor of Medicine Chulalongkorn University, and HIV-NAT, Thai Red Cross AIDS Research Centre

Targets of Antiretroviral Agents RT Inhibitors NRTI: AZT, ddi,

RNA DNA RT vpr ds DNA Integrase 3 Transcription Proviral DNA 4

RNA 5 6 HIV Protea Entry Inhibitors CCR5: Maraviroc Fusion gp41:

2 Targets of Antiretroviral Agents RT Inhibitors NRTI: AZT, ddi, ddc, d4t, 3TC, ABC NNRTI: NVP, EFV, ETV NTRTI: Tenofovir HIV 1 2 RNA DNA RT vpr ds DNA Integrase 3 Transcription Proviral DNA 4 mrna Protease Inhibitors ATV, DRV, fapv, LPV, rtv, SQV Genomic RNA 5 6 HIV Protea Entry Inhibitors CCR5: Maraviroc Fusion gp41: Enfuvirtide Spliced mrna Polyprotein Protein Integrase inhibitors Raltrigavir

3 In Reality: The Goal of durable HAART is Achievable Plasma HIV-RNA (copies/ml) 7 Male, on HAART for >10 years 1,000,000 Viral load CD4 100,000 10,000 1, AZT/3TC/NFV 246 VL < AZT/3TC/EFV 569 CD4 count (cells/mm3)

4 How to detect failure and DR? Time-course of HAART Failure Resistance CD4 drop Non- Adherence Viral load Clinical Started HAART Time after treatment

5 A Setting where with no CD4 VL monitoring 77 % Yr1 Patients on HAART (N=1187) Retrospective study <50 % Yr 5 age >15, Median CD4 BL =105, >50% WHO stage 3-4 Tropical Medicine and International Health, Jan 2009

6 N=48,785 Median Baseline CD4 = 118 cells/cu.mm. Only CD4 monitoring implemented (not with VL testing) After 5 years, 50% had immunologic treatment failure Ann Intern Med August 18, :I-42

7 We desperately need a low cost HIV- 1 viral load test and DR test for developing countries!

8 Definition of Virologic Failure The inability to achieve or maintain suppression of viral replication Setting Incomplete suppressionaft er 24 weeks DHHS 2012 WHO 2013 Thai NAP 2013 >200* >1000 NA Virologic Rebound >200*** >1000 >2000 Or confirmed >1000 *High Baseline VL (>100,000 c/ml) may take longer than low BL VL ***>200 is associated with evidence of viral evolution and drug-resistance mutation accumulation

Four Scenarios of Detectable Viremia after Virologic

Test History of ART and previous DR tests Change to 3 active

No need to change ART Development of resistance likely Try DR

9 Four Scenarios of Detectable Viremia after Virologic Suppression by HAART Viremia >1000 Thai NAP >2000 DR Genotypic Test History of ART and previous DR tests Change to 3 active ARV-regimen Low Viremia BLIP VL >200-<1000 VL No need to change ART Development of resistance likely Try DR test, consider change No consensus, FU over time DHHS Guidelines March 2012

Antiretroviral Regimens in Thai NAP Current follow up cases 131424 Patients on ART 118140 5% 95% First-line

10 Antiretroviral Regimens in Thai NAP Current follow up cases Patients on ART % 95% First-line ART Second-line ART 6000 currently on second-line ART National AIDS Program (NAP), Thailand. As of Dec 2010

NHSO Bangkok Region -Achievements NAP s treatment outcome target

59 hospitals Only 11 of 59 hospitals achieved the goal Achieved the

11 NHSO Bangkok Region -Achievements NAP s treatment outcome target Treatment targets 1. 75% of patients are tested for VL once a year, plus 2. 75% of patients tested have VL,50 c/ml 59 hospitals 19 % N=13,280 in 59 hospitals Only 11 of 59 hospitals achieved the goal Achieved the target 81 % Below the target Among 11 that reached the target 3 achieved 85% of VL<50% 8 achieved 75% of VL<50% Bangkok NHSO, March 2012

12 Identify, Assess and Address Treatment Failure

: Toxicogenomic Socioeconomic Life-style Drug Multi-comorbidity Psychiatric disorder Drug

13 Possible Causes of Treatment Failure Virus Transmitted resistance Superinfection with DR Doctor Experience Attitude Patient supporting Patient motivation Patient Adherence Genetics : Toxicogenomic Socioeconomic Life-style Drug Multi-comorbidity Psychiatric disorder Drug abuse Suboptimal potency wrong dose Risk of toxicity Drug-drug interaction Single vs multiple dosing

14 Transmitted ARV resistance is associated with a high risk of virologic failure

15 % patients with VL<50 c/ml GS-934 study: Baseline NNRTI-resistance compromises virologic responses Without With NNRTI-R At baseline TDF/FTC/EFV AZT/3TC/EFV Gallant JE eta l. NEJM 2006; 354:

16 TASER-M Results the TREAT Asia Studies to Evaluate Resistance- Monitoring Study % of patients N= 682 patients (Hong Kong, Malaysia, Thailand) Antiretroviral treatment-naïve Sungkanuparph S et al. Poster PE 3.1/3 12th EACS. Nov 11 14, Cologne, Germany

17 Viologic Failure and HIV Resistance

Genotypic HIV Resistance Test Practical considerations Should be done at the time while patients are taking the regimen or have been stopping for <4 weeks Viral load level >1000 c/ml Reliable

18 Genotypic HIV Resistance Test Practical considerations Should be done at the time while patients are taking the regimen or have been stopping for <4 weeks Viral load level >1000 c/ml Reliable previous treatment history is essential when interpreting the DR test results Negative results can not exclude the undetectable minority resistance viruses (that <10-20%) Ideally for multiclass failure, phenotypic assay in addition will be more useful

What to start in Resource-rich settings?

19 What to start in Resource-rich settings? Three drug combination in Naïve Patients 2 Nucleoside RT Inhibitors + NNRTI or Boosted PIs NtRTI or NRTI TDF ABC AZT d4t Cytidine Analog FTC + 3TC + NNRTI or Boosted PIs EFV Atazanavir/r Darunavir/r Raltegravir

20 What to start in Resource-limited settings? Three drug combination in Naïve Patients 2 Nucleoside RT Inhibitors + NNRTI or Boosted PIs NtRTI or NRTI TDF AZT d4t Cytidine Analog 3TC + FTC + NNRTI or Boosted PIs EFV NVP

21 Resource-rich Settings (RRS) vs Resource-limited Settings (RLS) RRS RRS RLS RRS RVLS RLS RRS: First-line HAART 2 NRTIs: TDF/FTC 3 rd ARV: EFV, ATV/r, RAL, DRV/r Lab monitoring DR baseline, VL + CD4 >3/yr RLS: First-line HAART 2 NRTIs: d4t or AZT/3TC >TDF/FTC 3 rd ARV: NVP> EFV Lab monitoring CD4 : <2/yr VL: most countries no, some 1/yr

mutation assays Phenotyping: Cost 800-1000 USD

22 HIV Drug ResistanceTesting Genotyping Different platforms Dideoxy sequencing Gene chip Point mutation assays Phenotyping: Cost USD Recombinant virus assays Virtual phenotyping Bioinformatics

23 HIV drug Resistance Assay Principles Patient derived PR-RT coding sequences C G A T G T Automated sequencing Computer analysis Genotypic Resistance Report PR-RT deleted HIV-1 genome Homologous recombination Viable Virus Phenotypic Resistance Report

Genotypic Assay Dideoxyterminator Sequencing Nucleotide sequence result CCTCAGATCACTCTTTGGCAACGACCCATAGTCACAATAAAGATAGCGGGACAACTAAAGGAAGCTCTATTAGATACAGGAGCAGATG

24 Genotypic Assay Dideoxyterminator Sequencing Nucleotide sequence result CCTCAGATCACTCTTTGGCAACGACCCATAGTCACAATAAAGATAGCGGGACAACTAAAGGAAGCTCTATTAGATACAGGAGCAGATG ATACAGTATTAGAAGAAATGAATTTGCCAGGAAAATGGAAACCAAAAATAATAGTGGGAATTGGAGGGTTTACCAAAGTAAGACAGT ATGATCATGTACAAATAGAAATCTGTGGACATAAAGTTATAGGTGCAGTATTAATAGGACCTACACCTGCCAATATAATTGGAAGAAATC TGTTGACTCAGCTTGGCTGTACTTTAAATTTT Amino acid sequence result PQITLWQRPIVTIKIAGQLKEALLDTGADDTVLEEMNLPGKWKPKIIVGIGGFTKVRQYDHVQIEICGHKVIGAVLIGPT PANIIGRNLLTQLGCTLNF Differences from Consensus HIV-1 subtype B: L10I, G17R, K20I, E35D, N37S, M46I, I62V, L63P, A71I, G73S, I84V, L90M, I93L

25 Amino Acid SLC DNA codons Isoleucine I ATT, ATC, ATA Leucine L CTT, CTC, CTA, CTG, TTA, TTG Valine V GTT, GTC, GTA, GTG Phenylalanine F TTT, TTC Methionine M ATG Cysteine C TGT, TGC Alanine A GCT, GCC, GCA, GCG Glycine G GGT, GGC, GGA, GGG Proline P CCT, CCC, CCA, CCG Threonine T ACT, ACC, ACA, ACG Serine S TCT, TCC, TCA, TCG, AGT, AGC Tyrosine Y TAT, TAC Tryptophan W TGG Glutamine Q CAA, CAG Asparagine N AAT, AAC Histidine H CAT, CAC Glutamic acid E GAA, GAG Aspartic acid D GAT, GAC Lysine K AAA, AAG Arginine R CGT, CGC, CGA, CGG, AGA, AGG Stop codons Stop TAA, TAG, TGA

26 What dose L90M mean?

27 Efavirenz K 103N V 106M Y 188L G 190SA Etravirine L 100I k 101P Y 181CI Nevirapine V 106M Y 181CI Y 188L G 190SA

NNRTI resistant mutations Efavirenz K 103N V 106M Y 188L G

181CI Y 188L G 190SA Rilpivirine E 138K Rilpivirine RAMs E138K

7-fold reduced phenotypic susceptibility to rilpivirine E138K

28 NNRTI resistant mutations Efavirenz K 103N V 106M Y 188L G 190SA Etravirine L 100I k 101P Y 181CI Nevirapine V 106M Y 181CI Y 188L G 190SA Rilpivirine E 138K Rilpivirine RAMs E138K and M184I showed 6.7-fold reduced phenotypic susceptibility to rilpivirine E138K alone. 2.8 folds reduction K103N alone was not associated with reduced susceptibility to rilpivirine. IAS-USA Nov 2011

29 Resistance Mutations Selected by NRTIs Abacavir K K65R 65 R L 74 V Y 115 F M M184V 184 V Didanosine K K65R 65 R L 74 V Emtricitabine K K65R 65 R M M184V 184 VI Lamivudine K K65R R M M184V 184 VI Stavudine M 41 L E 44 D K D K K65R R N R TAMs V 118 I L T K W YF QE Tenofovir K K65R 65 R Zidovudine M L 41 E 44 D D K N R TAMs V 118 I L T K W YF QE Johnson A et al

Multi-NRTI Resistance Mutations Multi-nRTI Resistance (TAMs) M 41 L D K 67 70 N R TAMs L T K 210 215 219 W YF QE Multi-nRTI Resistance: 69 Insertion Complex M 41 L A 62 V K 69 70 Insert R 69iSS,

30 Multi-NRTI Resistance Mutations Multi-nRTI Resistance (TAMs) M 41 L D K N R TAMs L T K W YF QE Multi-nRTI Resistance: 69 Insertion Complex M 41 L A 62 V K Insert R 69iSS, Q151M L T K W YF QE Affects all NRTIs except TDF Multi-nRTI Resistance: 151 Complex A 62 V V 75 I F 77 L F 116 Y Q 151 M TAMs Plus M184V = whole class resistance TAMs 41, 67, 70, 210, 215, 219 Johnson A et al

Percent DART Study Evolution of resistance on therapy WHO treatment guidelines If HIV RNA monitoring not available, switch to second-line therapy for fall of CD4+ count to pre-treatment baseline or

31 Percent DART Study Evolution of resistance on therapy WHO treatment guidelines If HIV RNA monitoring not available, switch to second-line therapy for fall of CD4+ count to pre-treatment baseline or fall of 50% from peak value WHO guidelines are not sensitive for detecting virologic failure DART virology substudy from Uganda and Zimbabwe (n=377) ZDV/3TC + TDF for 48 weeks with limited prospective laboratory monitoring Retrospective genotype testing Viremic patients with TAMs TAMs 0 TAMs 1 3 TAMs Week 24 Week Plasma HIV RNA <1000 c/ml in 63% of patients at 48 weeks Baseline resistance in 10% of those analyzed: NRTI, 6%; NNRTI, 4% Persistent viremia resulted in increasing TAMs between Weeks 24 and 48 Pillay D, et al. 14 th CROI, Los Angeles 2007, #642

32 Resistance profiles in NNRTI-based failure Higher VL (>4 log) was associated with more TAMs, MDR and K65R ns ns P<0.05 P<0.05 P<0.01 ns TAMs K65R Q151M Sungkanuparph S, et al. Clin Infect Dis Feb1;44(3):

Prevalence of NNRTI-mutations in NVP vs EFV-based failure N=62 100 90 80 70 60 50 40 30 20 10 0 86 95 17 p<0.

33 Prevalence of NNRTI-mutations in NVP vs EFV-based failure N= p<0.001 NVP EFV n=42 n= Approximately up to 50% cross resistance to etravirine (ETR) 41 20

34 Don t let HAART failure continuing without action You will loss the whole ARV class sooner!

35 Thymidine-analogue mutations: TAMs IAS USA, Resistance mutation update Nov 2011

36 NNRTI-based failure NNRTI-RAMs: K103N, Y181C/I, Y188L, G190G/A, V106M. L10I, K101E 0 1 RAM 2 RAMs >2 RAMs Number of RAMs Number of susceptible NNRTI Time on failing ART NVP EFV ETV RPV ETV RPV 0

37 NRTI-based failure Number of RAMs TAMs =Thymidine analog-associated mutations 0 3TC-R M184V 1-3 TAMs >3 TAMs 3TC, FTC AZT, d4t, ddi, ABC, TDF AZT, d4t ddi, ABC, TDF d4t, ddi ABC, TDF TDF 0 Time on failing ART Number of susceptible NRTIs

38 How to choose a second regimen after NNRTI-based failure?

39 Choosing Options after first-line 2NRTIs+ NNRTI-based failure Treatment failure NNRTIs NRTIs PIs INI EI Early Late Very Late Duration of taking failing regimens (arbitrary cut-off) Early <6 months Late >6 mo -1 yr Very late >1 yr

40 Treatment options after a NNRTI-regimen Failure Resource rich settings NRTI TDF? ABC? ddi? NNRTI ETR? RPV? II RAL EVG* (Quad pill) PI ATV/r, DRV/r, FPV/r, IDV/r LPV/r, SQV/r, TPV/r EI ENF MVC N=20 U.S. FDA approved ARVs (EVG as quad pill is pending)

41 Treatment options after a NNRTI-regimen Failure A Resource-limited setting: Thailand -NAP NRTI TDF? ABC? ddi? PI LPV/r, ATV/r,

42 Randomized studies to address appropriate treatment options for NNRTI-based failure

43 Second-line ART controlled studies Study N comparators Sites Sponsors End point analysis HIV-STAR 200 TDF/3TC +LPV/r LPV/r mono Thailand 10 sites NHSO, Swiss cohort Nov 2011 SECOND- LINE 550 2NRTI +LPV/r RAL +LPV/r All continents 18 countries Kirby Insitute, Australia Sept 2012 ALISA 386 TDF/FTC +LPV/r TDF/3TC +ATV/r 2LADY 450 TDF/FTC +LPV/r ABC/ddI +LPV/r TDF/FTC +DRV/r EARNEST NRTIs +LPV/r RAL +LPV/r LPV/r mono (assessed 22 Apr 2012) Africa SA, Tanzania Africa Burkina Faso, Cammaroon, Senegal Africa 5 countries French NIH May 2013 ANRS12169 Sep 2013 MRC, EDCTP Dec 2013

44 HIV STAR N=200: TDF/3TC +LPV/r vs LPV/r alone HIVNAT initiated, sponsor: NSHO and Swiss Cohort

45 The HIV-STAR Study NNRTI failure VL 1000 copies/ml LPV/r N =100 TDF/3TC + LPV/r N=100 Randomization will be stratified by baseline HIV RNA 5 log and CD4 < 100 cells/mm3

46 HIV-STAR : Baselines Parameter Mono-LPV/r TDF/3TC/LPV/r N = 98 N =97 Age (years) 36.8 (6.8) 38.2 (6.9) n(%) male 66 (67%) 47 (48%) % CDC clinical classification A:B:C 25:20:55% 22:24:54% % nevirapine : efavirenz 88 : 12 % 84 : 16 % Duration of NNRTI-based HAART before enrollment (years) 1.8( ) 2.3( ) Baseline CD4 count (cells/mm3) 194 (123) 211 (134) Baseline HIV-RNA (log 10 c/ml) 4.1 (0.6) 4.1 (0.6) % of patients with M184V/I 83.7% 80.4% K65R 6.1% 7.2% 3 TAMs 31.6% 25.8% multi NRTI resistance 13.3% 21.6%

47 % Virological suppression HIV-STAR: Percentage of patients with virological suppression at week HIV-RNA copies/ml 61% p< % Mono-LPV/r TDF/3TC/LPV/r P <400 75% 86% <200 69% 86% 0.01 <50 61% 83% <0.01 HIV-RNA 400 copies/ml HIV-RNA <400 copies/ml HIV-RNA <200 copies/ml HIV-RNA <50 copies/ml Intention-to-treat (ITT) analysis

48 % patients with plasma HIV-1 < 50 c/ml HIVStar Results Patients with baseline GSS 2 had a better VC rate *P< * Mono LPV/r GSS 1 GSS 2 TDF/FTC/LPV/r arm Number of active ARV(s) in the regimen No. of subjects =

49 Thymidine-analogue mutations: TAMs IAS USA, Resistance mutation update Nov 2011

50 Thymidine-analogue mutations: TAMs TAM-1 TAM-2 IAS USA, Resistance mutation update Nov 2011

215Y ) 70R Subtype non-b CRFO1_AE 67N 70R 219Q/E Lower-level AZT and d4t resistance Less NRTI cross-resistance Not resist to TDF TAM-2

51 Dichotomous Pathways in the Evolution of TAMs Zidovudine or Stavudine Subtype B TAM-1 41L 215Y 210W 215Y Higher-level AZT and d4t resistance More NRTI cross-resistance More TDF resistance (esp. 215Y ) 70R Subtype non-b CRFO1_AE 67N 70R 219Q/E Lower-level AZT and d4t resistance Less NRTI cross-resistance Not resist to TDF TAM-2 Subtype C: a mixed TAM1/2 pathway Bunupuradah, et al. HIVSTAR results(submission) Novitsky V, et al. AIDS Res Hum Retroviruses. 2007; 23: Clavel F and Hance AJ. HIV Drug Resistanc. N Engl J Med 2004; 350:

52 % of patients with viral load < 50 c/ml HIV-STAR Results Patients who had TAM2 but not TAM1 or K65R showed a benefit when adding TDF LPV/r monotherapy TDF/3TC/LPV/r 90.9 * 90.9 * 72.2 Any TAM1 Any TAM2 3 TAM2 Resistance-associated mutation (RAM) *p <0.05 n= 17/15 49/48 18/15

53 Predictors of Virological Failure Multivariate logistic regression analysis Adjusted predictor HIV-RNA 5 log 10 c/ml at time of failure OR (95% CI) 6.2 ( ) LPV/r monotherapy 2.5 ( )

54 Choosing a new regimen for patients who fail their first-line NNRTI-regimen in Resource-rich settings First-line TDF/FTC/EFV ABC/3TC/EFV Failure GT guided Second-line 2 NRTIs + DRV/r 2 NRTIs + ATV/r 2 NRTIs + LPV/r Combined New Classes 2 NRTIs + RAL 2 NRTIs + ETV, RVP RAL+ LPV/r RAL+ other PIs? MVC + PIs + RAL?

55 Lesser options for patients failed their first-line NNRTI-regimen in RLS? First-line d4t/3tc/nvp AZT/3TC/NVP AZT/3TC/EFV Failure GT guided?? Second-line 2 NRTIs + LPV/r TDF/3TC+ LPV/r No TAM1, no K65R TDF/3TC/EFV Failure GT guided?? AZT/3TC + LPV/r AZT/ABC+ LPV/r Should not use mono-lpv/r

56 Choosing 2 new classes combination: RAL+bPI? in NNRTI-failure

Second-line Study NCHECR, Sydney A Randomised Open-label Study Comparing the Safety and Efficacy of Ritonavir Boosted Lopinavir and 2-3N(t)RTI Backbone Versus Ritonavir Boosted Lopinavir and

57 Second-line Study NCHECR, Sydney A Randomised Open-label Study Comparing the Safety and Efficacy of Ritonavir Boosted Lopinavir and 2-3N(t)RTI Backbone Versus Ritonavir Boosted Lopinavir and Raltegravir in Participants Virologically Failing First-line NNRTI/2N(t)RTI Therapy N = 550 NNRTI-based failure Raltegravir + LPV/r 2-3 NRTIs + LPV/r Expected results At 48 weeks Sep 2012 ERNEST study : N=1277, RAL/LPV/r vs LPV/r mono vs LPV/r/TDF/FTC Expected48 weeks results; Dec 2013

58 PROGRESS Study : Primary Efficacy Endpoint at Week 48 Proportion of Subjects Responding (FDA ITT TLOVR) LPV/r + RAL was non-inferior to LPV/r + TDF/FTC in treatment-naïve subjects at 48 weeks

59 HIV Protease Inhibitor Drug Resistance Update 2013 Kiat Ruxrungtham Professor of Medicine Faculty of Medicine, Chulalongkorn University; and HIVNAT, Thai Red Cross AIDS Research Center

60 HIV Protease Mutations Selected by PIs Atazanavir +/- r Darunavir/r Fosampre navir/r Indinavir/r Lopinavir/r IAS-USA HIV resistance update. Top HIV Med. 2011

61 Mutations Selected by PIs (cont) Nelfinavir Saquinavir/r Tipranavir/r Overall major RAMs: 13 Overall minor RAMs: 31 IAS-USA HIV resistance update. Top HIV Med. 2011

62 Major and Minor RAMs of Various PI PI Major RAMs Minor mutations ATV 4 20 DRV/r 5 5 FPV 2 9 IDV 3 11 LPV/r 4 13 NFV 2 8 SQV 2 9 TPV 6 8 Data based on IAS-USA HIV resistance update. Top HIV Med. 2010;18(5):

63 Major and Minor RAMs of Various PI PI Major RAMs Minor mutations ATV 4 20 DRV/r 5 5 LPV/r 4 13 Data based on IAS-USA HIV resistance update. Top HIV Med. 2011

64 Mutation Scoring <10 Susceptible >10-20 potential low R Low level R intermediate R >60 High level R

65 12 major PRAMs Position WT MT FPV/r IDV/r NFV SQV/r LPV/r ATV/r TPV/r DRV/r 30 D N V I M I/L I A/V / G V I V I L I M L V V T I V L M

66 12 major PRAMs Position WT MT LPV/r ATV/r DRV/r 30 D N V I M I/L I A/V 50/ G V I V I L I M L V V T I V L M

67 Universal PRAMs: V82T, I84V, L90M Are these relevant for LPV/r, ATV/r, DRV/r? They are relevant in cross-pi resistance mainly among first-generation PIs: SQV, NFV, IDV, TPV But they have low level cross resistance to second-generation PIs: V82T, L90M: low level cross resistance to LPV/r, ATV/r I84V has also cross resistance to ATV/r, but has much less affect on LPV/r All 3 PRAMs has no or very little (I84V) affect on DRV/r susceptibility

68 Boosted PI-based failure Number of RAMs PRAMS >5-10 PRAMs >10 PRAMs LPV/r, ATV/r, SQV/r, IDV/r FPV/r,DRV/r LPV/r, ATV/r, SQV/r, IDV/r FPV/r,DRV/r DRV/r 0 Time on failing ART Number of susceptible bpis

69 You don t need to worry for how to memorize these complicated PRAMs? The DR-genotypic test report will do all the interpretation for you!

70 AZT/3TC/NVP M46L, I84V, L90M Note: This case was a firstline NNRTI-failure, but had carried multi-pi DR. This indicates that he had been acquired primary PI-resistance.

71 Choosing Options after first-line 2NRTIs+ bpi-based failure

72 RAMs in NNRTI- vs PI-based Treatment Failure Meta-analysis of 20 clinical trials : 30 treatment arms and 7970 patients Incidence of resistance associated mutations at week NNRTI-based p<0.001 bpi-based P=0.01 p< VF M184V K65R NNRTI or PI Paredes R, Clotet B. Antiviral Research 85 (2010)

73 Resistance After Virologic Failure in the CASTLE and ARTEMIS Studies at 96 Wks Characteristic ATV/RTV + TDF/FTC (n = 440) CASTLE [1] ARTEMIS [2] LPV/RTV + TDF/FTC (n = 443) DRV/RTV + TDF/FTC (n = 343) LPV/RTV + TDF/FTC (n = 346) Virologic failures, n Genotypic assays, n Major PI mutation, n NRTI mutations, n Major PI RAM is uncommon in early first PI-based failure 1. Molina JM, et al. J Acquir Immun Defic Syndr. 2010;53: Mills A, et al. AIDS. 2009, 23: From Joseph Eron, CCO 2010

74 PI-treatment Failure of the HIVNAT Cohort (n=90) PI-HAART NNRTI/bPI* 2NRTIs/nbPI** 2bPI* Others*** number Median CD4(cell/mm 3 ) baseline CD at recent failure current CD Median VL(copies/mL) baseline VL at recent failure Current VL < 50 < 50 < 50 < 50 < 50 Failing Regimen 1 st line failure nd line failure rd line failure th line failure Current Regimen 2NRTI/1NNRTI NRTI/1PI NRTI/1NNRTI/1PI Others(new drugs, 2NRTIs/1nbPI, 2NRTIs/2bPI) Surasarit Khawlaor, Allergy Immunology Fellow

75 PRAMs found in PI-failure of the HIVNAT cohort PI-mutation number codon TOTAL 69 GENOTYPING ANALYSIS PI-RAMs 21 Major PI-RAMs for DRV I47V 0 I50V 0 L76V 0 I84V 0 Major PI-RAMs for ATV I50L 0 I84V 0 N88S 0 Major PI-RAMs L90M 1 V82M 1 Any PI-RAMs 0 K20R 4 M36I 9 L33I 1 Surasarit Khawlaor, Allergy Immunology Fellow

76 How to treat patients failed multiple classes of ARVs?

77 How all of the treatmentexperienced trials were designed?

78 BENCHMRK 1 & 2 RAL in Treatment-Experienced Patients Week 16 primary analysis Week 48 current analysis Week 156 planned follow-up HIV-infected patients with triple-class resistance and HIV-1 RNA > 1000 copies/ml (BENCHMRK-1: N = 352; BENCHMRK-2: N = 351) RAL 400 mg BID + OBR* (BENCHMRK-1: n = 232; BENCHMRK-2: n = 230) Placebo + OBR* (BENCHMRK-1: n = 118; BENCHMRK-2: n = 119) *Investigator-selected OBR based on baseline resistance data and history; inclusion of DRV and TPV permitted.

79 DUET-1 & -2: Phase III Trials of ETR + DRV/RTV-Containing OBR HIV-infected patients with VF on current HAART regimen with history of 1 NNRTI resistance mutations, 3 primary PI mutations, and HIV-1 RNA > 5000 copies/ml (DUET-1: N = 612; DUET-2: N = 591) Week 24 primary endpoint ETR 200 mg BID + DRV/RTV-containing OBR* (n = 599) Placebo + DRV/RTV-containing OBR* (n = 604) Week 48 *Investigator-selected OBR consisting of DRV/RTV 600/100 mg/day BID + 2 NRTIs ± ENF.

New drugs lead to improved outcomes for treatment-experienced patients 70 60 50 40 30 20 10 16 6 Active

MOTIVATE 1&2* DUET 1&2** *DRV/r not allowed in OBT **All received DRV/r ***wk 16 data, others wk 24

NEJM 2003; Hicks et al. Lancet 2006; Clotet et al. Lancet 2006; Nelson et al. CROI 2007; Lalezari et al.

80 New drugs lead to improved outcomes for treatment-experienced patients Active arm Control arm % <50 copies/ml TORO* RESIST* POWER* MOTIVATE 1&2* DUET 1&2** *DRV/r not allowed in OBT **All received DRV/r ***wk 16 data, others wk 24 BENCHMARK 1&2*** ENF TPV/r DRV/r MVC ETV RAL (+DRV/r) Lalezari et al. NEJM 2003; Lazzarin et al. NEJM 2003; Hicks et al. Lancet 2006; Clotet et al. Lancet 2006; Nelson et al. CROI 2007; Lalezari et al. CROI 2007; Madruga et al. Lancet 2007; Lazzarin et al. Lancet 2007; Cooper et al. CROI 2007; Steigbigel et al. CROI 2007

HIV-1 RNA < 50 copies/ml (%) POWER 3 Study Darunavir fold change 10 and

higher % of HIV-1 RNA < 50 copies/ml at Week 24 100 80 60 40 20 0 n = P <.

0036 55 54 50 48 27 22 17 18 9 170 88 33 35 178 68 74 37 49 82 Darunavir

81 HIV-1 RNA < 50 copies/ml (%) POWER 3 Study Darunavir fold change 10 and HIV-1 RNA 100,000 copies/ml at baseline significantly associated with a higher % of HIV-1 RNA < 50 copies/ml at Week n = P <.0001 P <.0001 P = Darunavir Fold Change HIV-1 RNA, log 10 copies/ml CD4+ Cell Count, cells/mm 3 Molina JM, et al. J Acquir Immune Defic Syndr. 2007;46: Adapted from CCO 2008

82 More recent treatment-experienced studies recruited more earlier failing patients with higher BL CD Median Baseline CD4 cell count (cells/ l) Study ARV ENF ETR RAL DRV/r MVC DRV/r DRV/r DRV/r/ETR/RAL

83 More recent treatment-experienced studies recruited more earlier failing patients with lower VL at baseline Median Baseline plasma HIV-RNA (log10 c /ml)

84 Virologic Responses in Treatmentexperienced Trials (most data at 48 wks) % patients with VL<50 Wk 96 Wk Active 50% 37% <33% 75% 17% ARVs 2

85 TRIO study Re-suppression to VL<50 is feasible in multidrug resistance N=103 RAL + DRV + ERV addition of NRTIs, ENF at discretion of physician 48 weeks 86% of patients had VL <50 Inclusion criteria included susceptibility to DRV and ETR based on 3 DRV and 3 ETR RAMs 60% of patients had < 1 additional active agent (by GSS) Yazdanpanah et al CID 2009; 49:1441 9

86 Raltegravir + Etravirine + Maraviroc REMStudy In Patients with Multi-class Failure (Analogy to TRIO study: RAL/ETR/DRV/r with a high rate of VL<50 c/ml)

87 96 Durability of 28 multi-class failure patients on Ral/ETR/MVC (REM study) % patients with VL <50 c/ml 93% 96% Median CD4 increased from baseline CD4 increased 278 CD4 increased 211 Nozza et al. JAIDS 2011 ; 56:e113-e115 (letter to editor)

88 Key Factors Determine the success for viral re-suppression of a new regimen Number of active ARV in the regimen Baseline drug resistance if the same class of ARV will be used Baseline VL level: VL<100,000 Baseline CD4 count: CD4>100 Adherence Tolerability

Conclusions Early detection of VF is critical to preserve the next treatment option Selecting a new regimen for a treatment failing patient is based on History (ARV exposure, DR

89 Conclusions Early detection of VF is critical to preserve the next treatment option Selecting a new regimen for a treatment failing patient is based on History (ARV exposure, DR results), adherence, drugdrug interaction, comorbidities, and the availability of active ARVs To aim for a durable re-suppression of VL<50, the new regimen should consist of ideally 3 active drugs

90 Thank You

Kiat Ruxrungtham. Professor of Medicine Chulalongkorn University, and HIV-NAT, Thai Red Cross AIDS Research Centre

Kiat Ruxrungtham. Professor of Medicine Chulalongkorn University, and HIV-NAT, Thai Red Cross AIDS Research Centre Kiat Ruxrungtham Professor of Medicine Chulalongkorn University, and HIV-NAT, Thai Red Cross AIDS Research Centre www.iasusa.org; www.aidsinfo.nih.gov; www.clinicaloptions.com; www.clinicaloptions.com/hiv