Advanced Resistance Issues for the Clinician

Transcription

1 Advanced Resistance Issues for the Clinician Stephen Raffanti MD MPH CMO, Comprehensive Care Center Associate Director HIV Clinical Services Vanderbilt University School of Medicine

2 Goals of this talk Work with the essentialcomponents of retroviral resistance in a pragmatic, clinical approach; Discuss (yes that means audience participation!) real life cases; Come away with a feasible approach to maximizing available knowledge and resources to get the best outcomes for your patients. Have a little fun.

3 First some important terms (and ones you can ignore) Resistance: how we describe the changes the virus makes to replicate in the presence of external factors: Clinically significant mutations in appropriate genes; Clinically insignificant mutations in appropriate genes (polymorphs); Net phenotypic change from above mutations; Changes in receptor tropism; Immunologic al escape mechanisms;* Efflux mechanisms;*» *not extremely helpful for clinicians at this point

4 Retrovirus Life Cycle Co-receptor, CD4 binding inhibitors Maraviroc Vicriviroc TNX 355 Fusion Inhibitors Enfuvirtide Protease inhibitors SQV IDV RTV NFV FPV LPV ATV TPV DRV Reverse transcriptase inhibitors ZDV NVP ddi DLV ddc EFV d4t 3TC FTC ABC TDF Etravirine Rilpivirine Integrase inhibitors Raltegravir Elvitegravir (GSK364735)

5 Genotype Assay PATIENT PLASMA (>200 µl) Viral PR/RT gene isolation total RNA cdna extraction RT PCR PR/RT GENES (amplicon) Sequence interpretation C T A G C A C GT Automated DNA sequencing Codon Mutation Silent mutation AAA GAC AGT AAA AAC AGC Lys Asp Ser Lys Asn Ser

6 Phenotype Assay Resistance Test Vector DNA Transfect vector DNA into cell PR RT IN Patient derived Segment Resistance Test Vector DNA Luciferase Indicator Gene + A MLV env DNA Infection PR Inhibition RT Inhibition

7 New dx, ART naive

8 Current Rx: ZDV/3TC, NVP HIV RNA 45,000, CD4+ 350

9 Phenotype

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11 Resistance Remember no matter how you measure it, you are probably talking about the dominant strain in a swarm of strains. It is only one of the ones that matter now.

12 First some important terms (and ones you can ignore) Fitness: a measure of how well a virus replicates in a certain environment or with certain changes (mutations): Ask me about my MG

13 First some important terms (and ones you can ignore) Fitness can be measured: in the lab: Replicative capacity in the patient Current viral load It can explain some phenomena: Meds that shouldn t be active having gan impact: 3TC, maybe NRTI s, maybe PI s, Duration of resistance mutations of meds.

14 Partial Treatment Interruptions (N= 65) (Change in Viral Load) 1.0 Change 0.5 Plasma HIV RNA (week 2) NRTI PI NNRTI Fusion Discontinued Treatment Class Deeks 2005

15 Fitness For the most part measuring it is not important. forget about it

16 First some important terms (and ones you can ignore) Minority variants and dominantstrains: HIV replicates at very high rates: virions a day; HIV polymerases have a very high error rate: approx. 1 mutation per genome per cycle; In addition to mutations, recombinations occur between diploid genomes in each virion; Every possible mutation and many double mutations are generated in each individual every day. New assays are available that can detect minor variants down to <1% of replicating strains (point mutation assays, ultradeep pyrosequencing); The presence and magnitude of some minor drug resistant variants has been associated with treatment failure in naïve and treated patients.

17 First some important terms (and ones you can ignore) Current role of supersensitive assays for minor variants: Not yet ready for prime time.

18 Six easy rules to Select the Best Regimen for your patient Know the history; ( nohelp here just goodold old fashioned medicine, old records) Know the math; (all sorts of tools, charts and websites) Know the meds; (keep updated, especially drug drug interactions) Know the patient; (you are probably very good at this) Create your virus; (make the dreaded MDR HIV) Test your hypothesis. (treat the patient, monitor response and if necessary, regroup)

19 James, energetic motivational speaker and rodeo rider It is James has been diagnosed with HIV for 5 years he has been treated off and on withtwomeds two meds. His current CD4 count is 362/22% Who is Secretary of State? What is the number one pop hit? What meds was he probably exposed to? Any ideas on the likelihood of resistance mutations and what they mightbe?

20 1991 (Everything I Do) I Do it for you. Bryan Adams

21 Mutations Selected by nrtis Abacavir Didanosinei Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine

22 James, successful real estate agent and songwriter It is In 1994 James developed hypertension and is being treated for depression. He was screened for a new clinical trial comparing two drugs (AZT/3TC) with 3 drugs (AZT/3TC/Indinavir). He is enrolled in study, stays on meds for 34 weeks until he develops kidney stones and drops out of care. Now his CD4 count is 262/18%, HIV 1 RNA is 64,320. What is the most important information we can get without a genotype? Do we need him to be unblinded?

23 James and the Clinical Trial Patient was unblinded: randomized to AZT/3TC and Indinavir Date CD4 Count CD4 % HIV 1 RNA 2/ ,330 6/ ,243 10/ ,240 1/ / ,200

24 James and the Clinical Trial Any idea about possible resistance mutations?

25 Mutations Selected by nrtis Abacavir Didanosinei Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine

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27 James, Round Three James undergoes genotypic testing after being off meds for about 7 months: RT: 44D, 41L, 215V, PRO: 36I, 77I, What other mutations tti are you worried idabout?

28 James, Round Three Most likely significant background mutation: 1) RT K65R 2) RT 103N 3) RT 184V 4) PRO 90M

29 The Special Case of M184V M184V emerges rapidly in nonsuppressive regimens containing 3TC or FTC Associated with high level phenotypic resistance to 3TC/FTC in vitro but also reduction in replication capacity, HIV RNA < baseline Increases susceptibility to ZDV, d4t, TDF Decreases susceptibility (slightly) to ABC, ddi Clinical impression: all NRTIs retain some activity

30 M184V I S tibilit t M184V Increases Susceptibility to d4t, ZDV, and TDF

31 3TC Alone vs Treatment Interruption in Patients Failing 3TC Based Rx Mean VL Increase (ITT) Mean CD4+ Decrease (ITT) Mean Cha ange in HIV-1 RNA (log 1 0 copies/ml L) 2.0 3TC (n = 29) TI (n = 29) P = Weeks n CD4+ s/mm 3 ) an Change in l Count (cell Mea Cell Weeks TC (n = 29) TI (n = 29) In contrast to treatment interruption arm, 3TC alone resulted in Smaller recovery e in replication capacity No further selection of resistance mutations P = NS Castagna A, et al. AIDS. 2006;20:

32 James, Round Four James is started on stavudine, didanosine and nelfinavir. He remains on this regimen until his leg pain becomes so severe that he stops all meds. He sees you in He has been off meds for 4 years. He is doing poorly, recently discharged from the hospital after an admission for esophagitis and pneumonia. He is homeless, living in a shelter.

33 James, Round Four James sees you in clinic and is eager to get back on ART. His meds include fluconazole, dapsone and amitriptyline. Would you order resistance testing? Date CD4 count CD4 % HIV 1 RNA O1/ ,290 06/ <400 11/ <400 02/ ,240

34 James, Round Four No resistance testing is available. What regimen would you choose? Stavudine, tenofovir, kaletra; klt Tenofovir, didanosine, efavirenz; Tenofovir, lamivudine, kaletra; Tenofovir, lamivudine, efavirenz.

35 James, Round Five James stayed on his current regimen off and on for another four years. He is successfully employed as a motivational speaker and has traveled extensively. In 2008 he suffered an acute MI. He stopped his HAART when he started his heart meds. His current meds include lisinopril, pravastatin, glypizide and plavix. It is 2009, he wants to start a new regimen, had some diarrhea with the last. He has been off HAART for 5 months.

36 James, Round Five Is it worth doing resistance testing? Date CD4 Count CD4 % HIV 1 RNA 3/ ,320 4/ <50 2/ <50 1/ ,234

37 James, Round Five James genotype shows thefollowing: RT: 103N, 188L, 41L, 44D, 69S, 74V, 215V; PRO: 32I,36I, 36I 47V, 50V, 77I, 82A; What do you do now? Hint: you can call a friend

38 Darunavir (Prezista) mutation score 3 or more baseline mutations from a list of 11 3 or more baseline mutations from a list of 11 specific mutations

39 Virologic Response by Number of PREZISTA Resistance associated Mutations at Baseline RNA <50 co opies/ml k 24 Patients (% %) with HIV-1 at wee % 22% 10% 0-2 mutations 3 mutations 4 mutations Based on supportive analyses of POWER 1, 2, and 3 examining patients achieving viral load <50 copies/ml at week 24.

40 Etravirine Resistant Scores 1 st Gen 2 nd Gen 1 st Gen

41 Response by Number of DUET Etravirine RAMs 80 Y181C 80 G190A % pts confirm med VL <5 50 c/ml No mut *(ref)* Y181C + 0 Etravirine RAMs No G190A mut *(ref)* Etravirine RAMs Patients t (n) ) *no detectable baseline NNRTI RAMs from the list of 44 Vingerhoets J, et al. Antiviral Therapy 2007;12:S34. Abstract 32.

42 James, Round Five What do you recommend for the next regimen? get a Trofile assay and represent; lopinavir/rtv, raltegravir, etravirine; atazanavir/rtv, raltegravir, etravirine; darunavir/rtv, raltegravir, etravirine;

43 James, Round Five James is about to be started on his regimen: Darunavir/rtv, etravirine and raltegravir Anything else you want to do?

44 Putting It All together How can all these factors be taken into account when designing a regimen? Patient factors: concurrent diagnoses, tolerances, adherence, insurance status; Viral factors: phenotype of current dominant strain, archived strains, viral fitness; Medication factors: dosing, drug interactions, short and long term toxicities.

45 Comprehensive Care Center ART Conference All patients either starting, stopping or changing antiretroviral therapy; Presentation includes past regimens withlabs, tolerances, genotypes, phenotypes; All co morbidities included; Patient preferences included; Wide participation of clinical staff. Available at

46 ART Conference Questions Should patient be treated? What are the goals of treatment? What other information i is important bf before designing an effective regimen? What is the greatest obstacle to success? What should be done and in what order?

47 Final Thoughts Prior and current phenotypes and genotypes are critically important components of designing a successful regimen. A complete review of past meds, labs, co morbidities and tolerances is essential. Once a predictably successful regimen is decided dupon, giving ii the patient the appropriate time and support to succeed is equally important.

48 AIDS 1985 One Patient s Experience 322 IVinsertions 8 intubations 14 hospital admissions 4 lumbar punctures 11 months of hospital stay 3 bone marrows 60 phlebotomies 5 cycles of chemo 32 chest x rays 5 CT scans of head 3 abdominal ct scans 6 bronchoscopies 2 lymph node bx

49 Useful HIV Websites (DHHS, USPHS/IDSA Guidelines com co

50 Gerry 46 year old male with chronic renal lithiaisis, hypertension, depressive disorder and recurrent HSV. His current medications include acyclovir, ramipril, hydrochlorothiazide, tmp smx, hydrocodone, emtricitabine, darunavir, ritonavir, enfuvirtide. He would like to discontinue his T 20 injections. i

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57 Gerry Patient discontinues the T 20 and continues on the darunavir /rtv and FTC. He begins raltegravir and etravirine. His HAART pill burden is five pills in the morning and six pills in theevening evening. His CD4 count is 732/24% and HIV 1 RNA is <48 copies/ml.

58 Erika 43 year old female with depressive disorder, treated breast cancer, hypertension, and obesity is presented for virologic failure. Her current medications include: valsartan, dapsone, mirtazapine, gabapentin, amitriptyline, didanosine, nevirapine and kaletra.

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64 Etravirine Resistance Score 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 = M230L = 2.5 erikas s score = 3.5 (50%)

65 Erika Patient discontinues her current regimen. Her sulfa allergy was considered but it was associated with a questionable, mild skin rash. She begins darunavir/rtv, raltegravir and maraviroc. She is seen by the CPS team and has weekly calls to review meds and adherence. Her current labs are CD4 count of 407/22% and HIV / 1 RNA is <40 copies/ml.