Management of Treatment-Experienced Patients: New Agents and Rescue Strategies. Joel E. Gallant, MD, MPH Johns Hopkins University School of Medicine

Transcription

1 Management of Treatment-Experienced Patients: New Agents and Rescue Strategies Joel E. Gallant, MD, MPH Johns Hopkins University School of Medicine

2 When to Modify Therapy! Studies to date show better responses with earlier switches, as well as viral evolution at low-level viremia

3 Resistance Evolves Even With Stable Low-Level HIV Viremia! 80% of patients with VL <10,000 developed new RT or PI mutations over 8 months 1» Most common NRTI mutations: K70R, D67N, V118I, L74V! 90% of patients with VL <1,000 developed resistance over 14 months 2» Resistance to all on-treatment ARV was associated with VL increases >1000 ( progressive failure ) 1 Kantor, 9th CROI; 2002; Seattle. Abstract Coakley 9th CROI; 2002; Seattle. Abstract 556.; 2002;

4 Evolution of NRTI Resistance with Ongoing Virologic Failure (CNA 3005: AZT + 3TC + ABC) Plasma HIV-1 1 RNA Log Wild-Type 5000 c/ml 400 c/ml 50 c/ml M184V Only 28 Weeks ABC=5.9 ZDV=4.1 fold Accumulation of TAMs D67N/D, K70R/K, M184V M184V, Y215T/Y L41L/M, M184V, Y215Y L41L, L41L, M184V, M184V, Y215Y Y215Y L41L, M184V, L210L/W, Y215Y ABC=6.2 ZDV=12.2 fold Study Week Melby T, et al. 8 th CROI. Chicago, Abstract 448.

5 When to Modify Therapy! Studies to date show better responses with earlier switches, as well as viral evolution at low-level viremia! The risk of emergence of new mutations is highest in patients with little resistance

6 When to Modify Therapy! Studies to date show better responses with earlier switches, as well as viral evolution at low-level viremia! The risk of emergence of new mutations is highest in patients with little resistance! Early modification is especially important with regimens that contain low genetic barrier drugs (e.g. NNRTIs, 3TC, FTC)

7 HIV Lifecycle and Drug Targeting NRTI Target NEJM 340 (21), p.1620

8 NRTI Sequencing Options After Failure of Specific NRTI Backbones Initial Regimen AZT/3TC d4t/3tc AZT/3TC/ABC TDF/3TC TDF/FTC Likely Resistance Pattern M184V +/- TAMs M184V +/- K65R Most Active NRTIs Depends on number of TAMs and TAM pattern TDF or ddi may be most active NRTIs AZT + TDF + either 3TC or FTC (Resistance may be less common with FTC) ABC/3TC M184V +/- either L74V or K65R AZT + TDF + either 3TC or FTC Choose the next NRTIs based on resistance testing.

9 HIV Lifecycle and Drug Targeting NNRTI Target NEJM 340 (21), p.1620

10 NNRTI Resistance! Resistance mutations common at virologic failure» May occur as 1 st mutation, preceding M184V! Limited prospects for sequential use of current NNRTIs:» Poor results from NVP failure with 181C EFV» G190A/S, P225H cause DLV hypersusceptibility, but no clinical sequencing data» 2 nd generation NNRTIs promising: TMC125, TMC278

11 TMC125-C223: Virologic Response to Etravirine in Pts With NNRTI and PI Resistance OBR Alone (n = 40) Etravirine 400 mg BID (n = 80) Etravirine 800 mg BID (n = 79) 0.4 Weeks Mean (± SE) Change in VL (log 10 c/ml) [ITT: NC=F] * -1.18* *P <.05 Grossman HA, et al. ICAAC Abstract H- 416c.

12 TMC125-C223: NNRTI Mutations and Response to Etravirine at Week 24 Mean change in viral load (log 10 c/ml) TMC mg bid Active control N=79 N= *All subjects had NNRTI mutations from prior genotyping Baseline NNRTI mutations in TMC mg bid 0* N=15 N=18 N=17 N= Vingerhoets J, et al. 13th CROI, Denver, CO, February 5-5 8, Abst Relevant NNRTI Mutations: K101P, V179E, V179F, Y181I, Y181V, G190S, M230L

13 HIV Lifecycle and Drug Targets PI Target NEJM 340 (21), p.1620

14 Resistance Patterns after PI Failure Unboosted PIs! NFV:» 30N: no cross-resistance» 90M: cross-resistance! SQV:» 48V: no cross-resistance» 90M: cross resistance! ATV:» 50L: no cross-resistance! IDV:» Various mutations causing cross-resistance! FPV» I54L/M, V32I + I47V: Variable cross-resistance RTV-Boosted PIs! No PI resistance after failure of:» LPV/r» FPV/r» SQV/r» ATV/r Choose the next PI based on resistance testing.

15 Resistance at Time of First Virologic Failure TC 3TC 3TC 3TC Patients (%) TAMs NFV 3TC 20 TAMs IDV APV 0 ZDV 1 3TC ABC (n=39) ZDV 2 3TC IDV (n=17) ZDV 3 3TC APV (n=16) d4t 4 3TC NFV (n=96) d4t 4 3TC LPV/r (n=51) 1 Melby T. 8 th CROI, Abstract 448; 2 Havlir D, et al. JAMA. 2000;283: ; 3 Rusconi S, et al. Antiviral Ther ;3: Kempf D. 10 th CROI. Boston, Abstract 600

16 RESIST-1: Superior Virologic Responses With Tipranavir/Ritonavir Responders, % Patients with 1 log 10 VL reduction (ITT, NC=F) TPV/r (n = 311) CPI/r (n = 309) Wks 41.5% 22.3% P <.0001 Hicks C, et al. ICAAC Abstract 1137a.

17 Relationship of TPV Score to TPV Phenotype Results and Response TPV Score Median Change in VL at Wk 24 (log 10 copies/ml) (n = 144) (n = 242) (n = 260) (n = 68) (n = 4) TPV Score Mutations 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V *24-week data from patients in RESIST-1 and -2 given TPV/r. Valdez H, et al. Resistance Workshop Abstract 27.

18 POWER: Subgroup Analyses of Response to Darunavir/r 600/100 BID Overall ENF Used (Naive) ENF Not Used 3 Primary PI Mut No Sensitive ARVs in OBR Darunavir/r 600/100 BID POWER-1 Cohort [1] 53% (n = 60) 18% (n = 60) 63% (n = 19) 22% (n = 18) 56% (n = 34) 19% (n = 36) 59% (n = 29) 9% (n = 35) 17% (n = 12) 0% (n = 9) Control POWER-2 Cohort [2] 7% (n = 53) 7% (n = 14) 30% (n = 20) 4% (n = 24) 7% (n = 28) 0% (n = 7) 18% (n = 11) 39% (n = 57) 35% (n = 23) 64% (n = 14) Patients with VL < 50 c/ml at Week 24 (%) (ITT NC=F) Patients With VL < 50 c/ml at Week 24 (%) Katlama C, et al. IAS Abstract WeOaLB Wilkin T, et al. ICAAC Abstract H-413.

19 Effect of Baseline Resistance on Response to Darunavir % With VL < 50 c/ml CPI Darunavir Overall Number of BL PI resistance-associated mutations (IAS-USA)! BL mutations associated with diminished response (< 33% with VL < 50 c/ml)» V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V (highlighted mutations emerged on therapy)» Presence associated with a higher number of PI mutations» Darunavir response remained higher than that of CPI DeMeyer S, et al. CROI Abstract 157.

20 HIV Lifecycle and Drug Targeting Entry Inhibitor target NEJM 340 (21), p.1620

21 gp 41 env Mutations Associated With Enfuvirtide Resistance: IAS-USA 2005 Enfuvirtide G 36 I 37 V 38 Q 39 Q 40 N 42 N 43 First heptad repeat (HR1 Region) D S V A M E R H T D

22 Maraviroc: Change in HIV RNA 0.5 Last day of dosing Change from baseline (log 10 HIV-1 copies/ml) Baseline Study A / UK-427,857 dose Placebo 015 Placebo mg QD 50 mg BID 100 mg QD 100 mg BID 150 mg BID Fast 150 mg BID Fed 300 mg QD 300 mg BID Time (day) n Fätkenheuer G et al.15 th IAC Abstract TuPeB4489

23 Update on CCR5 inhibitors Aplaviroc (GSK)! Phase IIb/III trials recently stopped due to hepatotoxicity! 4 (1%) treatment-emergent grade 3/4 ALT and total bilirubin >1.5x ULN Vicriviroc (Schering-Plough)! Study in ART-naïve stopped because of high rate of failure vs. EFV! May have been due to study design! Studies in experienced patients ongoing Maraviroc (Pfizer)! Studies ongoing in naive and experienced patients! 1 case with increased LFTs under review

24 TNX-355: Novel Entry Inhibitor! Anti-CD4 monoclonal antibody blocks gp120 attachment to CD4 receptor» Delivered by IV infusion! Phase II randomized trial in 82 3-class experienced patients [1]» TNX OBR or OBR alone» TNX-355 doses: 15 mg/kg IV every 2 wks 10 mg/kg IV every wk x 8 wks, then 10 mg/kg every 2 wks Mean Change in VL at Week 24 (log 10 c/ml) OBR alone TNX OBR 15 mg/kg (P =.003) 10 mg/kg (P <.001) Norris D, et al. ICAAC Abstract LB2-26..

25 HIV Lifecycle and Drug Targets Integrase Inhibitors NEJM 340 (21), p.1620

26 Integrase Inhibitor: MK-0518 Triple-class resistant by genotype/phenotype CD4 > 300 cells/mm³ VL > 5000 c/ml Placebo (n = 43) MK BID (n = 40) MK BID (n = 42) MK BID (n = 42) All combined with OBR No Active PIs, % Weeks! Multicenter, double-blind randomized study! Preliminary data reported! Endpoints» HIV-1 RNA, CD4 counts at 16 weeks» Safety! No boosting effect of ritonavir with this compound 16 Grinsztejn B, et al. CROI Abstract 159LB.

27 MK-0518: Viral Suppression < 400 c/ml Through Week Observed data Patients With VL < 400 c/ml (%) MK mg MK mg MK mg OBT alone Week Grinsztejn B, et al. CROI Abstract 159LB.

28 MK-0518: Viral Suppression < 50 c/ml Through Week Observed Data Patients With VL < 50 c/ml (%) MK mg MK mg MK mg OBT alone Week ! Adverse events similar to placebo Grinsztejn B, et al. CROI Abstract 159LB

29 HIV Lifecycle and Drug Targets Maturation Inhibitors NEJM 340 (21), p.1620

30 Maturation Inhibitors (PA-457): Blocks cleavage of capsid precursor to mature p24 Viral Budding and Maturation

31 PA-457: Virologic Response to Novel Maturation Inhibitor Monotherapy! Randomized, phase IIa study of 10-day monotherapy in 32 HIV-infected pts PL (n = 8) PA-457 Dose (mg/d) 25 (n = 6) 50 (n = 6) 100 (n = 6) 200 (n = 6)» Med. 1 log 10 VL reduction with PA mg/d! Generally well tolerated Median Change in VL at Day 10 (log 10 c/ml) (P =.02) (P =.004) (P <.0001) Beatty G, et al. ICAAC Abstract H- 416d.

32 Goals of Therapy With Multi-Drug Resistant HIV! Access to 2 active agents:» Completely suppress viral load» Now applies to an increasing number of salvage patients! Access to < 2 active agents:» Reduce viral load by >1 log 10» Stabilize CD4 count» Minimize drug toxicity» Prevent clinical progression and death» Avoid new resistance mutations that could eliminate future options» Avoid monotherapy with new drugs

33 Considerations for Salvage Therapy! In combination therapy, only the active drugs count

34 In Combination Therapy, Only the Active Drugs Count Patients with HIV RNA < 400 c/ml at Week 48 (%) 100 ENF + OB OB * * P <.05 0 * 30 8 DC + VF = Failure * * ENF: OB: Baseline GSS * 25 Miralles D, et al. ICDT- HIV 2004.

35 Considerations for Salvage Therapy! In combination therapy, only the active drugs count! A new drug may not be an active drug

36 Considerations for Salvage Therapy! In combination therapy, only the active drugs count! A new drug may not be an active drug! When to use a new drug, and when to wait

37 When to Use a New Drug, and When to Wait! What is prognosis with continued nonsuppressive therapy?! What are the resistance consequences of continued non-suppressive therapy?! How can I maintain the right mutations without allowing the wrong ones to emerge?! When will new drugs be available, and will they be active against the patients virus?

38 CD4-VL Disconnect: Can Impaired Fitness Be Used Strategically? CD Transient Complete Weeks Log HIV RNA Deeks. J Infect Dis 2000;181:946.

39 Continued Therapy in Patients With Virologic Failure: A Delicate Balance Maintain mutations Decrease fitness Delay progression Accumulate new mutations Develop resistance to drugs in development

40 Considerations for Salvage Therapy! In combination therapy, only the active drugs count! A new drug may not be an active drug! When to use a new drug, and when to wait! Waiting: Choosing a holding regimen

41 The Cost of Treatment Interruption in Treatment-Experienced Patients VL* Median Change in (log 10 c/ml) Median Change in CD4 Count (cells/mm 3 ) n = n = Weeks Before and After WT Switch *3 subjects excluded because baseline VL near upper LOQ Deeks SG, et al. N Engl J Med. 2001;344:

42 Partial Treatment Interruption Discontinue PIs, continue NRTIs (n = 15) Discontinue NRTIs, continue PIs (n = 5) Change in HIV-1 RNA (log 10 copies/ml) l Change in CD4+ Cel Count (cells/mm 3 ) Wk 8 Wk 12 Wk Wk 8 Wk 12 Wk Deeks SG, et al. J Infect Dis. 2005;192:

43 Guidelines for Choosing a Non- Suppressive Holding Regimen! Never use an NNRTI» NNRTI mutations have no beneficial impact on fitness» Accumulation of additional mutations may result in crossresistance to 2 nd generation NNRTIs! Always use 3TC or FTC» Simple and well tolerated drugs» M184V decreases fitness» Increased activity of AZT, d4t, TDF! Choose PIs and/or NNRTIs based on resistance and tolerability/toxicity considerations

44 Timeline for New Antiretrovirals Entry inhibitors (anti-gp120, CCR5) Maturation inhibitors Integrase inhibitors CXCR4 inhibitors Integrase inhibitors CCR5 inhibitors PA Darunavir Etravirine TMC278 Dexelvucitabine Brecanavir PIs NNRTI NRTI

45 Using of New Agents: Too Soon, Too Late, or Just Right?! Too soon:» New drug used in combination with inactive or partially active drugs despite relatively preserved CD4 count! Too late:» New drug deferred until the patient s virus is resistant to all other available drugs! Just right:» New drug combined with other active new agents, or use deferred until other new agents available

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