History (August 2010) Therapy for Experienced Patients. History (September 2010) History (November 2010) 12/2/11

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1 (August 2010) Therapy for Experienced Patients Hiroyu Hatano, MD, MHS Assistant Professor of Medicine University of California San Francisco Medical Management of AIDS December M HIV (CD4=450, VL=6250, LPV/r/EPZ/TDF), transferring care from another clinic Has been on ARVs with few interruptions since 1986, when he took ZDV for several months Has been on current regimen for ~4 years VL usually undetectable but thinks VL recently increased because missing a few doses Had a genotype done at prior clinic and there are some medications that I m resistant to (September 2010) CBC, Chem7, LFT s all WNL CD4= /25% VL= , reports excellent ARV adherence with LPV/r/EPZ/TDF (November 2010) Reports friend died suddenly from cancer Friend was also employer, so patient has lost his job as well (CD4 not done) VL= , reports 100% adherence with LPV/r/EPZ/TDF 1

2 (February 2011) Labs from previous visit not done Patient got new job and feeling better, but still having problems paying rent CD4= /25% 506/27% VL= (April 2011) Pt misses interim visit Labs not done at previous or current visit CD4=506/27%, VL=208, reports 100% adherence with LPV/r/EPZ/ TDF (April 2011) Previous genotype (?date) finally obtained from prior clinic NRTI: M41L, K65R, D67N, V75I, Q151M, K219R, T215M NNRTI: V90I, K101Q, V108M, Y181C, H221Y PI: L10I, K20I, M46I, G73C, I84V, L90M (April 2011) Patient clearly has drug resistance, although setting of this previous genotype (date, timing in relation to current ARV regimen) unclear However, patient likes current regimen due to lack of side effects, and is reluctant to change ARV s Decision made to monitor Q3-6 months 2

3 (June 2011) Labs not done at previous visit CD4=506/27% VL=208 12,317, reports 100% adherence with LPV/r/EPZ/TDF (August 2011) Patient misses interim visit CD4=506/27% 500/27% VL=208 12, Given unknown setting of prior genotype, genotype repeated ZDV monotherapy, then LPV/r/EPZ/TDF for ~4yrs Does this patient have drug resistance? August 10 August 11 3

4 Mechanisms of Drug Resistance High Virus Turnover (10 9 virions/day) Random Mutations (Quasispecies) Error-prone Reverse Transcriptase ARV regimen (potency, adherence) Test Detects presence of specific drug resistance mutations in RT and PR regions of HIV genome Drug Pressure Drug Resistant Virus Decreased Genotypic/Phenotypic Susceptibility Decreased Viral Fitness Test First letter indicates amino acid for WT Number indicates codon position Second letter indicates amino acid for mutant A, alanine C, cysteine D, aspartate E, glutamate F, phenyalanine G, glycine H, histidine I, isoleucine K, lysine L, leucine M, methionine N, asparagine P, proline Q, glutamine R, arginine S, serine T, threonine V, valine W, tryptophan Y, tyrosine What does patient history tell us? Has been on ARVs with few interruptions since 1986, when he took ZDV for several months Presumably infected before 1986 with wild type virus ZDV monotherapy concern for TAM s 4

5 (August 2011) NRTI: NNRTI: V90I, K101Q, V108I, Y181C PI: L10I, K20I, M46I, G73C, T74S, I84V, L90M Trofile: R5 TAM s TAM s K65R 5

6 TAM s K65R Q151M complex TAM s NRTI Resistance: Thymidine Analog Mutations (TAM s) Occurs with prior treatment with ZDV, d4t Resistance to all NRTI s, depending on number and pattern 2 Pathways: M41L, L210W, T215Y frequency 2x higher D67N, K70R, T215F, /E TDF still active K65R 6

7 NRTI Resistance: K65R Occurs with prior treatment with TDF, ABV, d4t, ddi Resistance to TDF and ABV Bidirectional antagonism : TAMs and K65R are rarely detected in same patient sample TAMs decrease likelihood of K65R K65R causes hypersusceptibility to ZDV Q151M complex NRTI Resistance: Q151M Complex NRTI Resistance: Q151M Complex 7

8 TAM s K65R Q151M complex Expect only minimal (if any) activity from NRTI s Should we include any NRTI s in the new regimen? 3TC Decreased activity given TAM s and Q151M complex Benefits: Reduced viral fitness Partial virologic activity ( 0.5 log 10 ) HBV co-infection Risks: Very little, if any NNRTI mutations: V90I, K101Q, V108I, Y181C NNRTI mutations: V90I, K101Q, V108I, Y181C EFV, NVP 8

9 NNRTI mutations: V90I, K101Q, V108I, Y181C EFV, NVP ETV Etravirine 2 nd generation NNRTI FDA-approved in 2008 High genetic barrier to resistance Resistance is cumulative with increasing mutations V90I, A98G, L100I*, K101E/H/P*, V106I, E138A/G/K, V179D/F/T, Y181C*/I*/V*, G190S/A, M230L ETR Mutation Weight Factor V90I 1 = A98G 1 = L100I 2.5 = K101E 1 = K101H 1 = K101P 2.5 = V106I 1.5 = E138A 1.5 = V179D 1 = V179F 1.5 = V179T 1 = Y181C 2.5 = Y181I 3 = Y181V 3 = G190A 1 = G190S 1.5 = M230L 2.5 = Score Etravirine Weighted Resistance Score Weighted Mutation Score Week 24 response rates in DUET trials % (highest response) % (intermediate response) > % (reduced response) PI mutations: L10I, K20I, M46I, G73C, T74S, I84V, L90M Total weighted ETR mutation score = ETV will not be fully active Vingerhoets J, et al. International HIV Drug Resistance Workshop; 2008; Sitges, Spain. Abstract 24. 9

10 PI Resistance Primary mutations Emerge first, decrease antiviral effect Secondary mutations Emerge later, increase fitness of strains with primary mutations or further decrease antiviral effect Specific primary and secondary PI mutations, depending upon PI What are the preferred 2 nd line PI s? TITAN study Treatment-experienced, LPV/r-naive patients 31% PI-naive N=595 randomized to DRV/r BID vs LPV/r BID ITT: DRV superior to LPV: 71% vs 60% VL <50 at 48 weeks Madruga et al, Lancet 2007;370:3-5 PI Resistance: DRV Resistance Associated Mutations (DRV-RAMs) V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V DRV response diminished with 3 DRV-RAMs PI Resistance PI mutations: L10I, K20I, M46I, G73C, T74S, I84V, L90M De Meyer et al, AIDS Res Hum Retroviruses. 2008;24:

11 PI Resistance PI mutations: L10I, K20I, M46I, G73C, T74S, I84V, L90M DRV-RAM DRV should be at least partially active Integrase Inhibitor Resistance 1 of 3 pathways: Q148H/K/R + (L74M, E138K, G140S) N155H + (L74M, E92Q, T97A, Y143H, G163K/R, V151I, D232N) Y143R/H/C Transmitted Integrase Resistance Trofile: R5 MVC should be fully active RGV should be fully active IAS 2010 TUPE163 11

12 What is the next best treatment option? 1. Continue LPV/r/EPZ/TDF 2. Switch to DRV/r/ETV/3TC 3. Switch to RGV/DRV/r/3TC 4. Switch to RGV/ETV/3TC 5. Switch to RGV/DRV/r/ETV/3TC 6. Switch to RGV/DRV/r/MVC/3TC 7. Switch to RGV/DRV/r/ETV/MVC/3TC 8. Stop ARV s CD4=500, VL=868 NRTI: M41L, K65R, D67N, V75I, F77L, Q151M, NNRTI: V90I, K101Q, V108I, Y181C PI: L10I, K20I, M46I, G73C, T74S, I84V, L90M Trofile: R5 How did this patient develop so much drug resistance? Has been on ARVs with few interruptions since 1986, when he took ZDV for several months Presumably infected before 1986 with wild type virus ZDV monotherapy, then LPV/r/EPZ/TDF for ~4 years Pt reports good adherence ZDV monotherapy TAM s Compromised activity of EPZ/ TDF On functional monotherapy with LPV/r Delfraissy et al, AIDS 2008;22: PI: L10I, K20I, M46I, G73C, T74S, I84V, L90M Did delay in changing ARV s lead to any deleterious effects? ZDV monotherapy, then LPV/r/EPZ/TDF for ~4yrs LPV mutations August 10 August 11 12

13 What is risk of continuing partially suppressive regimen? At 1 year: 23% developed new NRTI mutation 18% developed new PI mutation 30% lost phenotypic equivalent of 1 susceptible ARV Probably less risk if already have multiple mutations at baseline 1 new Major PI Mutation 1 new NRTI Mutation Any new Mutation Hatano, et al, CID 2006;43: What is the next best treatment option? 1. Continue LPV/r/EPZ/TDF 2. Switch to DRV/r/ETV/3TC 3. Switch to RGV/DRV/r/3TC 4. Switch to RGV/ETV/3TC 5. Switch to RGV/DRV/r/ETV/3TC 6. Switch to RGV/DRV/r/MVC/3TC 7. Switch to RGV/DRV/r/ETV/MVC/3TC 8. Stop ARV s CD4=500, VL=868 NRTI: M41L, K65R, D67N, V75I, F77L, Q151M, NNRTI: V90I, K101Q, V108I, Y181C PI: L10I, K20I, M46I, G73C, T74S, I84V, L90M Trofile: R5 What is the next best treatment option? 1. Continue LPV/r/EPZ/TDF 2. Switch to DRV/r/ETV/3TC 3. Switch to RGV/DRV/r/3TC 4. Switch to RGV/ETV/3TC 5. Switch to RGV/DRV/r/ETV/3TC 6. Switch to RGV/DRV/r/MVC/3TC 7. Switch to RGV/DRV/r/ETV/MVC/3TC 8. Stop ARV s CD4=500, VL=868 NRTI: M41L, K65R, D67N, V75I, F77L, Q151M, NNRTI: V90I, K101Q, V108I, Y181C PI: L10I, K20I, M46I, G73C, T74S, I84V, L90M Trofile: R5 Summary When changing ARV regimen, consider: Prior ARV history /Phenotype/tropism What ARV s was patient taking when tests were performed? Pill burden (adherence) Drug interactions Co-morbidities (HBV, renal insufficienty, hyperlipidemia) 13

14 Summary Benefit to continuing 3TC despite evidence of resistance Reduced viral fitness Partial virologic activity ( 0.5 log 10 ) HBV co-infection When changing ARV regimens, always consider what future drug options the patient will have Selected Website References DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, 10/14/11 AdultandAdolescentGL.pdf International AIDS Society-USA drug resistance mutation website mutations_figures.pdf HIV InSite Stanford University HIV Drug Resistance Database 14