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Failure of Antiretroviral Therapy and Subsequent Treatment Options

Failure of Antiretroviral Therapy and Subsequent Treatment Options. Rafael E. Campo, MD Associate Professor of Medicine University of Miami Leonard M. Miller School of Medicine and Jackson Memorial Hospital Miami, FL rcampo@med.miami.edu.

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Failure of Antiretroviral Therapy and Subsequent Treatment Options

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  1. Failure of Antiretroviral Therapy and Subsequent Treatment Options Rafael E. Campo, MD Associate Professor of Medicine University of Miami Leonard M. Miller School of Medicine and Jackson Memorial Hospital Miami, FL rcampo@med.miami.edu

  2. Failure of Antiretroviral Therapy and Subsequent Treatment Options • 1st line regimens • What are the recommendations? • How frequently do they fail? • What resistance can be expected if and once they fail? • What role do genetic barriers and pharmacokinetic characteristics of ARV agents play in the selection of resistance?

  3. Failure of Antiretroviral Therapy and Subsequent Treatment Options • 2nd line regimens • What is in the current ARV armamentarium? • What is the possible sequencing of regimens based on the components of the 1st regimen? • How likely is success with a 2nd and subsequent regimens? • How complex, costly, and efficacious are salvage regimens? • What is in the future drug pipeline?

  4. 1st line regimens: What are the recommendations?

  5. Recommended ARV Regimens for Treatment-Naïve Patients: DHHS October 2005 Preferred regimens Efavirenz* + (3TC or FTC) + (ZDV or TDF) Lopinavir/ritonavir + (3TC or FTC) + (ZDV) Alternative regimens PI-based Atazanavir + (3TC or FTC)+(ZDV or d4Tor ABC or ddI) or (TDF +RTV 100 mg/d) Fosamprenavir + (3TC or FTC)+(ZDV or d4T or ABC or TDF or ddI) Fosamprenavir/RTV† + (3TC or FTC)+(ZDV or d4T or ABC or TDF or ddI) Indinavir/RTV† + (3TC or FTC)+(ZDV or d4T or ABC or TDF or ddI) Lopinavir/RTV + (3TC or FTC)+(d4T or ABC or TDF or ddI) Nelfinavir + (3TC or FTC)+(ZDV or d4T or ABC or TDF or ddI) Saquinavir§/RTV† + (3TC or FTC)+(ZDV or d4T or ABC) NNRTI-based Efavirenz* + (3TC or FTC) + (ABC or ddI or d4T) Nevirapine‡ + (3TC or FTC) + (ZDV or d4T or ddI or ABC or TDF) Triple NRTI** Abacavir + 3TC + ZDV *Not recommended for use in 1st trimester pregnancy or women with high pregnancy potential. **Only when a preferred or alternative NNRTI- or PI-based regimen cannot or should be used as initial therapy. † Low-dose RTV (100–400 mg/day). ‡ Use with caution in women with pre-NVP CD4+ counts >250 and men with CD4 counts >400 cells/mm3. §soft gel or hard gel capsules Available at: http://aidsinfo.nih.gov/guidelines 6 October 2005

  6. 1st line regimens: How frequently do they fail?

  7. 100 p=0.005 80 FTC + TDF 81%* ZDV/3TC 70%* 60 % responder * 95% CI: (+3.4%, +18.1%) 40 Exclude NNRTI-R (n=487): FTC + TDF 84%, ZDV/3TC 73%, p=0.001 (+4.3%, +18.6%) 20 0 BL 8 16 24 32 40 48 GS 934: TDF + FTC + EFV vs ZDV/3TC + EFVPrimary Week 48 analysis % with HIV RNA <400 c/mL (TLOVR), ITT (n=509) • Open-label • ART-naïve patients (n=509) • Any CD4+ cell count • HIV RNA >10,000 c/mL • Randomized 1:1 • Non-inferiority trial 144 weeks Pozniak A et al. 3rd IAS, Rio de Janeiro 2005, #WeOa0202; Gallant JE et al.NEJM 2006; 354:251-260.

  8. 96-week, Latin American extension study enrolling pts completing 144 weeks in GS 903; n=86 92% OT (87% ITT) with VL <50 c/mL No patient developed K65R mutation through Week 192 Longest running prospective single-arm study; n=100 95% of subjects OT (59% ITT) with VL <50 c/mL No pt developed LPV or d4T resistance through Week 3603 92% 100 87% 95% (n=62) 80 % Patients with HIV RNA <50 c/mL 60 100 HIV RNA <50 c/mL 40 80 20 60 40 0 ITT M = F 0 60 120 180 240 300 360 20 ITT M = Excluded Week Week 0 0 24 48 72 96 120 144 168 192 ARV-Naïve Treatment:Long-Term Follow Up Gilead 903E (EFV + TDF + 3TC)1 % patients with HIV RNA <50 c/mL through Week 192 Abbott 720 (LPV/r + 3TC + d4T [TDF])2% patient with HIV RNA <50 c/mL through Week 360 (OT) 1 Enejosa J, et al. 10th EACS, Dublin 2005, #PE7.3/13; 2 Murphy R, et al. ibid, #PE7.9/3; 3 Da Silva B, et al. 7th Int Workshop on Adverse Drug Reactions & Lipodystrophy in HIV, Dublin 2005, #63

  9. Mean Change in CD4 cell Count through 312 Weeks +528 cells/µL Week N: 100 86 72 63 Landay A. et al.,3rd IAS, Rio de Janeiro, Brazil, #WePe16.7B04Study 720

  10. PI + NRTIs NRTItriple NNRTI+ NRTIs Boosted PI+ NRTIs 0 10 20 30 40 50 60 70 80 90 100 Efficacy of Modern ART: Virologic and Immunologic Response by Drug Class Week 48 response by drug class • ART-naïve patients in clinical trials 1994–2004 • 13,147 patients in 49 studies Week 48 HIV RNA <50 c/mL by treatment arm * p<0.01 vs NRTI and PI † p<0.05 vs PI ** p<0.01 vs NNRTI, NRTI, and PI # p<0.05 vs NRTI • Caveats: • Cross-study comparison • CD4+ responses may be impacted by lower baseline CD4+ counts in recent studies • Wide range of patient numbers (n=32–405) Response (%) Bartlett J, et al. 12th CROI, Boston 2005, #586

  11. 1st line regimens: What resistance can be expected if and once they fail?

  12. First Failure and Resistance • Drug resistant HIV in this population may be limited: 20-50% of patients may have no evidence of resistance1 • If present, resistance usually arises to the component(s) of the regimen with the lowest genetic barrier • 3TC • NNRTI: EFV, NVP, DLV • NFV • Resistance to unboosted but more potent PIs (e.g. indinavir) might be moderate • Resistance to ritonavir-boosted PIs may be very limited 1. Havlir D et al. New Engl J Med 1998; 339:1261-1268.

  13. Resistance at Time of First Virologic Failure 3TC 3TC 3TC 3TC EFV NNRTI + 3TC NFV Patients (%) NNRTI 3TC IDV TAMs TAMs APV 3TC TAMs IDV LPV (0%) TAMs TAMs (0%) TAMs (N/A) d4T4 3TC LPV/r (n=51) d4T4 3TC NFV (n=96) ZDV1 3TC ABC (n=39) ZDV2 3TC IDV (n=17) ZDV3 3TC APV (n=16) IDV5 EFV (n=14) ZDV6 3TC EFV (n=24) 1Melby T. 8th CROI, 2001. Abstract 448; 2Havlir D, et al. JAMA. 2000;283:229-234; 3Rusconi S, et al. Antiviral Ther. 1998;3:203-207. 4Kempf D. 10th CROI. Boston, 2003. Abstract 600; 5Holder DJ, et al. 6th CROI. Chicago, 1999. Abstract 492; 6Vavro C, et al. 42nd ICAAC. San Diego, 2002. Abstract H-2052.

  14. Genotypes after Virologic Failure of EFV + TDF + 3TC in ART Naïve Patients TDF/3TC/EFV (n=29 of 299) d4T/3TC/EFV (n=25 of 301) Wild-type or as baseline M184V alone EFV-R* alone EFV-R* + M184V EFV-R* + K65R EFV-R* + K65R + M184V EFV resistance = 48% * K103N, V106M, Y188C/L or G190A/S/E/Q 12 (48%) EFV-R • 8 (32%) M184V • 2 (8%) K65R 16 (55%) EFV-R • 12 (41%) M184V • 7 (24%) K65R Miller MD, et al. HIV6, Glasgow 2002, #P205

  15. Study 863 (LPV/r vs. NFV plus d4T/3TC): Incidence of Resistance at Weeks 24 – 96 HIV RNA above 400 copies/ml Genotype available Resistance detected in protease 3TC resistance LPV/r (n=326) 74 51 0/51 (0%) 19/51 (37%) NFV (n=327) 113 96 41/96 (43%) 79/96 (83%) • Absence of resistance to LPV confirmed by phenotypic analysis Walmsley S, et al. N Engl J Med 2002; 346:2039-46.

  16. Barrier to Resistance for Protease Inhibitors and NRTI’s Study Study Study 418 863 720 HIV RNA above 400 copies/ml 22 74 28 15/22 51/74 18/28 Genotypic results available 0/15 0/51 0/18 Lopinavir resistance † 0/15 NA NA TDF resistance ‡ NA 0/51 0/18 TAMS (D4T) resistance ‡ 3/15 19/51 3/18 3TC/FTC resistance § † LPV/r resistance: emergence of primary or active site mutation at protease positions 8, 30, 32, 46, 47, 48, 50, 54, 82, 84, 90, with phenotypic LPV resistance FC> 2.5 vs WT TDF resistance: emergence of K65R or any TAM (41, 67, 70, 210, 215, 219) in RT ‡ 3TC/FTC resistance: emergence of M184V mutation in RT § Molina JM, et al. XV IAC, Bangkok, Thailand, July 2004; WePe5701, Kempf Antiviral Therapy 2002;7:S119, D, et al. Gulick RM, et al. HIV7, Glasgow, UK, Nov. 2004; #P28

  17. Lack of Resistance to fos-APV/RTV: 48-Week Studies in Naïve Subjects (NEAT and SOLO) • fos-APV bid (NEAT) and fos-APV/r (SOLO) vs. NFV, all in combination with 3TC and ABC. • Analysis of prevalence of resistance to PIs, 3TC, and ABC. NEAT SOLO Elston R, et al. 2ndIAS, Paris 2003, #558

  18. 1st line regimens: What role do genetic barriers and pharmacokinetic characteristics of ARV agents play in the selection of resistance?

  19. 2nd line (and subsequent) regimens: What is in the current ARV armamentarium?

  20. Existing Classes : Licensed Drugs

  21. Naïve patient Experiencedpatient Highly- experienced patient Success Failure Success Failure Success Failure Potential ARV Regimens • 22 antiretroviral agents have been approved in the U.S. • Theoretically >600 triple-combinations can be made • However, due to cross-resistance and cross-toxicity, a limited number of regimens are available to an individual patient

  22. 2nd line (and subsequent) regimens: What is the possible sequencing of regimens based on the components of the 1st regimen?

  23. Therapy after Failure of 1st Line, Un-Boosted PI Regimen: Options • 2nd PI regimen (sparing NNRTIs) • Degree of NRTI resistance will be important • Serious consideration should be given to RTV-boosting • NNRTI-based regimen • Potent but fragile class • Degree of NRTI resistance very important • Triple class (PI/NNRTI/NRTI) • Few options will be left if there are tolerability, compliance, or resistance issues • Nucleotide intensification

  24. Therapy after Failure of 1st Line, NNRTI-Based Regimen: Options • PI-based regimen • Degree of NNRTI resistance important • Serious consideration should be given to RTV-boosting • Triple or quadruple nucleosides/nucleotides • Untested efficacy • 2nd NNRTI regimen • No currently licensed NNRTI can overcome NNRTI resistance; not an option

  25. Therapy after Failure of 1st Line, Triple NRTI Regimen: Options • PI-based regimen (sparing NNRTIs) • Degree of NRTI resistance important • Serious consideration should be given to RTV boosting • NNRTI-based regimen • Potent but fragile class • Degree of NRTI resistance very important • Triple class (PI/NNRTI/NRTI) • Few options will be left if there are tolerability, compliance, or resistance issues • NNRTI plus PI

  26. 2nd line (and subsequent) regimens: How likely is success with them?

  27. Time to Treatment Failure and Prevalence of Drug-Resistant HIV • Median time to treatment failure • 1st treatment regimen: 10.6 months • 2nd treatment regimen: 8.1 months • Subsequent treatment regimens: 6.4 months • Prevalence of HIV with reduced drug susceptibility among • Newly infected patients: 14% • Patients failing 1st triple combination: 75% • Patients failing multiple therapies: 95% Little SJ et al. New Engl J Med 2002;347:385-394. Boden D et al. JAMA 1999;282:1135–1141.Haubrich R et al. AIDS 2001;15:609-615.

  28. 2nd line (and subsequent) regimens: How complex, costly, and efficacious are they?

  29. 100 ENF+OB n=661 OB n=334 80 All comparisons ENF+OB vs OB p<0.001 60 Patients (%) 51 49 39 40 32.7 30.4 26 21 18.3 16 20 17 15.9 15 12 7.8 6.3 0 96 96 Week 24 48 24 48 24 48 96 CD4+ increase >50 cells/mm3 VL <400 c/mL VL <50 c/mL TORO 1 & 296-week follow-up % Responders at Weeks 24,1 482 and 96 (ENF+OB only)3 • Randomized (2:1), open-label trial of ENF (T-20) plus optimized background (OB) vs OB alone • Heavily experienced subjects (median 12 ARVs for 7 years) • BL HIV RNA 5.1 log10 c/mL • CD4 <100 cells/mm3 • 52% of subjects originally assigned to ENF+OB completed 96 weeks of study 1. Montaner J, et al. 2nd IAS, Paris 2003, #116; 2. Katlama C, et al. ibid, #LB2; 3. Arastéh K, et al. XV IAC, Bangkok 2004, #MoOrB1058 2 visits required to confirm virologic response

  30. Open-label, randomized, studies in USA (n=620)1 and Europe/Latin America (n=863)2 of TPV/r Entry criteria: >3 months’ therapy with NRTIs, NNRTIs, and PIs HIV RNA 1000 c/mL on therapy No CD4+ cell count restrictions Genotype indicated: >1 primary PI mutation at codons 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M and <2 mutations at codons 33, 82, 84, or 90 100 90 80 70 60 50 40 30 20 10 0 Time to treatment failure at Wk 48 (ITT NC=F) TPV/RTV CPI/RTV Estimated probability of remaining event-free 0 12 24 36 48 60 72 84 Weeks of exposure RESIST-1 and -2: 48-Week Pooled Analysis *Comparator PI ** Primary endpoint Cahn P, et al.10th EACS, Dublin 2005, #LBPS3/8

  31. 2nd line (and subsequent) regimens: What is in the future drug pipeline?

  32. Investigational Drugs: Existing Classes

  33. Investigational Drugs: New Classes

  34. 100 200 MK-0518 200 MK-0518 600 80 150 MK-0518 400 OBT Alone 60 100 % patients with HIV RNA <50 c/mL 50 40 Δ from BL in HIV RNA (log10 c/mL) Δ from BL in CD4+ cell count (cells/mm3) 0 0 20 -1 0 0 2 4 8 12 16 -2 Week MK-0518 200 mg 40 38 35 31 25 -3 MK-0518 400 mg 42 39 36 31 27 MK-0518 600 mg 42 40 35 32 28 0 2 4 8 12 16 OBT Alone 43 43 36 31 27 Week Integrase Inhibitor MK-0518 in Patients with Triple-Class ART Experience • Results presented for those with 16 weeks + follow-up • Only 2 patients lost to follow-up Proportion of patients (95% CI) with HIV RNA <50 c/mL Mean change from baseline (95% CI) in HIV RNA and CD4+ cell count Grinsztejn B, et al. 13th CROI, Denver 2006, #159LB

  35. 800 BID 50/100 QD 400 BID 800 QD 200 BID 1000 GS-9137 Plasma Concentration 100 10 IC * 50 0 6 12 18 24 Time (h) mean + SD * protein binding adjusted, wild type virus Mean change in HIV RNA 0.0 0.0 -0.5 -0.5 -1.0 -1.0 Placebo Placebo Log10 Change HIV-1 RNA 800 QD 800 QD -1.5 -1.5 200 BID 200 BID 10 400 BID 400 BID 800 BID 800 BID -2.0 -2.0 50 + RTV QD 50 + RTV QD Dosing Dosing Dosing -2.5 -2.5 BL BL 1 1 2 2 3 3 4 4 7 7 10 11 14 14 21 21 Day Day Pharmacokinetics and Antiviral Activity of Integrase Inhibitor GS-9137 Steady-state pharmacokinetics • Preclinical pharmacokinetics1 • Metabolized via CYP3A4; moderate inducer • 20-fold increased exposure with RTV 100 mg QD, 3-fold with food • Randomized, double-blind, placebo-controlled 10-day monotherapy study2 • Entry criteria: off ARV, CD4+ >200 cells/mm3, HIV RNA 10K-300K c/mL • 5 dosing cohorts, n=8 each; 6 active therapy, 2 placebo • No drug discontinuations or AEs different from placebo 1. Kawaguchi I, et al. 13th CROI, Denver 2006, #580; 2. DeJesus E, et al. ibid, #160LB

  36. Considerations Before Selecting ART for Extensively Experienced Patients

  37. Considerations Before Selecting ART for Extensively Experienced Patients • Low-level viral replication (<10,000 copies/ml) may need to be accepted as an outcome • The change to a new regimen after a 3rd or 4th failure should be paused and thoughtful • Viral load on a “failing” regimen may still reflect  from set point due to residual antiviral activity of partially active drugs • There might be clinically significant immunologic benefits associated with “failing” regimens • To “do nothing” (i.e. continue a “failing” regimen) while waiting for new drugs may be a valid option

  38. Questions and Discussion

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