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Update on HIV Pharmacotherapy

Update on HIV Pharmacotherapy. Objectives. Upon successful completion, participants will be able to: Discuss medications available for the treatment of HIV/AIDS disease Identify two possible drug interactions to be on the watch for. Epidemiology of AIDS in the U.S.

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Update on HIV Pharmacotherapy

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  1. Update on HIV Pharmacotherapy

  2. Objectives • Upon successful completion, participants will be able to: • Discuss medications available for the treatment of HIV/AIDS disease • Identify two possible drug interactions to be on the watch for

  3. Epidemiology of AIDS in the U.S. New AIDS diagnosis among the general U.S. population New HIV infections among men who have sex with men 43,500 8000 43,000 7500 42,500 42,000 7000 41,500 41,000 6500 40,500 MSM data are from 25 states with long standing HIV infection reporting systems 40,000 6000 1998 1999 2000 2001 2002 1998 1999 2000 2001 2002

  4. Combivir Viread Hivid Epivir Rescriptor Ziagen Retrovir Videx Zerit Viramune Sustiva Trizivir Emtriva Invirase Viracept Kaletra NRTI Fortovase Agenerase Reyataz nNRTI Norvir PI Crixivan Approved Antiretrovirals 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 Fuzeon FI

  5. HIV Life Cycle Fusion and entry Viral protease RNA RNA Proteins Reversetranscriptase RT RNA RNA DNA DNA RT DNA DNA DNA DNA Provirus Integrase

  6. Maximal and durable suppression of viral load Restoration and/or preservation of immunologic function Improvement of quality of life Reduction of HIV-related morbidity and mortality Maximize adherence Rational sequencing of therapy Preservation of future treatment options Use of resistance testing in selected clinical settings Goals of Therapy and Tools to Achieve Goals DHHS guidelines 7/2003 (www.AIDSinfo.NIH.gov)

  7. Obstacles to SuccessfulAntiretroviral Therapy • Antiretrovirals are unlikely to eradicate HIV • Treatment is life-long • Long-term toxicity • Mitochondrial toxicity • Lipid disorders • Body composition abnormalities • Drug Resistance DHHS guidelines 7/2003 (www.AIDSinfo.NIH.gov)

  8. HIV Treatment 2003 • Start therapy more cautiously. Make sure that patients understand the goals and the requirements of therapy. • Use simple, well tolerated regimens whenever possible. • Think of resistance pathways when choosing antiretroviral regimens. • Regimens should be maximally potent, which is necessary for long-term suppression. • Manage antiretroviral toxicities with risk-benefit ratio and quality of life in mind.

  9. Indications for Initiation ofTherapy: DHHS Guidelines DHHS guidelines 7/2003 (www.AIDSinfo.NIH.gov)

  10. Indications for Initiation ofTherapy: DHHS Guidelines DHHS guidelines 7/2003 (www.AIDSinfo.NIH.gov)

  11. Indications for Initiation ofTherapy: DHHS Guidelines DHHS guidelines 7/2003 (www.AIDSinfo.NIH.gov)

  12. Antiretrovirals Not Recommended for Initial Therapy DHHS guidelines 7/2003 (www.AIDSinfo.NIH.gov)

  13. Antiretroviral Caveats • Antiretroviral components not recommended: • Saquinavir hard gel capsule as single PI • Stavudine + didanosine in pregnancy • Efavirenz in pregnancy • Amprenavir oral solution in pregnancy, in children <4 years, in renal or hepatic failure, and in patients treated with metronidazole or disulfiram • Stavudine + zidovudine • Zalcitabine + stavudine • Zalcitabine + didanosine • Hydroxyurea DHHS guidelines 7/2003 (www.AIDSinfo.NIH.gov)

  14. Choosing the NRTI Backbone • Most NRTI combinations are equipotent • Avoid ddC due to toxicity • Avoid d4T + ZDV due to antagonism • Choice primarily based on tolerability • Cross-resistance among NRTIs more apparent • Less likely to sequence

  15. ESS30009 Study Design Open-label, randomized, multicenter trial Entry criteria •  18 years old • ART-naïve (14 days ART) • VL  5,000 copies/mL • No CD4+ restrictions 48 weeks EFV 600mg QD + ABC/3TC FDC QD n=180 planned Randomize* Screening TDF 300mg QD + ABC/3TC FDC QD n=180 planned Primary endpoint • Proportion with HIV-1 RNA <50 c/mL at week 48 *Randomization (1:1) stratified by HIV-1 RNA <100K or 100K c/mL

  16. ABC/3TC Fixed-Dose Combination • A fixed-dose combination (FDC) of ABC/3TC (600mg/300mg) is in Phase III development • Clinical and PK data support once-daily ABC • Piliero P, Poster A-1797, Tues 9/16, 3:00 - 4:30 PMIntracellular carbovir-triphosphate t1/2=20.64 hours • Gazzard B, Late-breaker H-1722, Tues 9/16, 4:10 PMRandomized, double-blind trial (N=770) of ABC QD vs ABC BID with 3TC QD and EFV QD • Once-daily 3TC approved by FDA and EMEA

  17. Unplanned Interim Analysis • Following rapid study accrual, several cases of early virologic non-response in the TDF + ABC/3TC arm were reported to GSK • Urgent unplanned interim analysis performed for subjects with 8 weeks HIV-1 RNA data (N=194 of 345 randomized patients) • Virologic non-response defined as: 1) <2.0 log decline in HIV-1 RNA by week 8 or 2) 1.0 log rebound from nadir at any subsequent visit or 3) Confirmed HIV-1 RNA >400 c/mL following two consecutive HIV-1 RNA <50 c/mL

  18. Baseline Characteristics For subjects with at least 8 weeks HIV-1 RNA data EFV + ABC/3TC TDF + ABC/3TC (N=92) (N=102) Median age, years 36.0 38.5 Male Sex 90% 92% Race Black / Hispanic / White 37% / 9% / 53% 29% / 9% / 62%CDC Class C 9% <1% Median HIV-1 RNA, log10 c/mL 4.71 4.53 Median CD4+ count, cells/mm3 280.5 251.5

  19. Proportion of subjects <50 c/mL For subjects with at least 8 weeks HIV-1 RNA data (observed analysis) 2 N =EFV arm 92 87 89 91 62 20TDF arm 102 99 100 101 62 17

  20. Week 12 NRTI Genotypic Mutations For subjects with virologic non-response to TDF + ABC/3TC (n=36*) NRTI resistance-associated mutations Other treatment emergent NRTI mutations present: V118I (n=3), Y115F (n=3). *Genotype unavailable for 14 subjects (11 without week 12 sample, 3 1000 c/mL)

  21. Proposed Hypotheses • Inadequate efficacy with once-daily ABC/3TC? • Unlikely given response with once-daily EFV + ABC/3TC • Efficacy & PK trials strongly support once-daily ABC/3TC • Drug interaction between TDF and ABC? • Pilot PK study (N=8) suggests no TDF effect on single-dose plasma ABC; further study warranted • Intracellular pharmacologic interaction? • Intracellular TDF assay N/A; currently under investigation • Low genetic resistance barrier to TDF + ABC/3TC? • Selection and outgrowth of minority population of pre-existing mutants may explain rapid failure and rebound • Currently under investigation

  22. Conclusions • TDF + ABC/3TC should not be used as a triple-combination regimen • Patients receiving this regimen should intensify or switch to an alternate regimen • Implications for regimens containing TDF + ABC/3TC with 4th agent (e.g. ZDV, PI, NNRTI) are currently under investigation • EFV + ABC/3TC shows promise as a two-pill, once-daily regimen; long-term data are forthcoming

  23. NNRTI NRTI NRTI Consideration for Initial Regimen PI NRTI NRTI

  24. HIV RNA Response ThroughWeek 60: M98-863 ** ** ** ** * * * <5064% 52% <400 74% 61% *p<0.05; **p<0.001 Week LPV/r n=326 NFV 327 41st ICAAC 2001; abstract I-1768

  25. MaxCmin2: study design Clinical indication for ritonavir-boosted PI treatment PI naivePI failurePI intolerance Randomization 1:1 LPV / r400/100 mg bid163 patients SQV / r1000/100 mg bid161 patients Dragsted et al. HIV6, 2002; poster PL14.5

  26. MaxCmin2: baseline characteristics PARAMETER LPV / rSQV / r Total (n=163)(n=163) (n=326) CDC, clinical cat. C (%) 3032 31 HIV-1 RNA (c/ml, median log10) 4.64.5 4.6 HIV-1 RNA <400 c/ml (%) 2220 21 CD4 count (cells/mm3, median)238 238 238 PI-naive (%) 4950 49 PI failure (400 c/ml (%)) 3232 32 PI intolerance (<400 c/ml (%)) 1918 19 Dragsted et al. HIV6, 2002, PL14.5

  27. MaxCmin2 trial: percentage of patients with HIV RNA <50 copies/ml at 48 weeks* On-treatment Intent-to-treat** p=ns p=ns 100 75% 80 70% 60% 53% 60 % patients 40 20 0 SQV / r SQV / r LPV / r LPV / r *analysis includes all patients who received randomized medication * * discontinuation of randomized therapy = failure

  28. 400 300 200 100 0 Baseline Week 4 Week 12 Week 24 Week 36 Week 48 Median CD4 Cell Count:MaxCmin 2 SAQ/r LPV/r 6 226 patients had a CD4+ increase of > 100 10 /l after a median of 85 days without difference in risk between the arms

  29. Criteria for Changing Therapy • Failure to suppress HIV RNA to undetectable levels w/in 4-6 months • Repeated detection of virus in plasma after initial suppression to undetectable levels • Any reproducible significant increase (>3-fold) of HIV RNA • Persistently declining CD4 counts • Clinical deterioration

  30. Randomized 2:1, then start FUZEON+OB or OB Screening period FUZEON+OB Sample for GT/PT† Stable regimen Switch permitted at virological failure – 6 – 4 OB Weeks BL 8 16 24 48 TORO 1 & 2: Protocol study design † GT = Genotypic Testing; PT = Phenotypic Testing

  31. Table 1. Combined TORO 1 and TORO 2: pooled baseline characteristics and prior ARV experience of study populations (ITT)

  32. Plasma HIV-1 RNA Adjusted Means LogChange from Baseline - Intent-to-TreatPopulation (LOCF) TORO 1 + TORO 2 Study week 24 0 -0.71 Change from baseline(log10 HIV-1 RNA copies/mL) -1  = 0.84 -1.55 P < 0.0001 -2 ENF + OB OB

  33. Percent Responders at Week 48 (ITT, DC+VF=Failure) 100 ENF + OB OB n = 661 n = 334 80 60 47.2 % Patients 40 32.7 24.9 20 15.9 15.0 6.3 0 Week 24 24 24  1 log10 drop from baseline < 400copies/mL < 50copies/mL * All ENF + OB vs. OB comparisons were statistically significant (P < 0.0001)

  34. 1.00 Median time to virologic failure 32 weeks (ENF + OB) vs.11 weeks (OB) (P < 0.0001) 0.75 Proportion without virologic failure 0.50 ENF + OB 0.25 OB 0.00 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Time to virologic failure (weeks) The time to protocol defined virologicalfailure was longer on FUZEON+OBcompared to OB

  35. CD4+ Cell Count Adjusted Means Changefrom Baseline - Intent-to-Treat Population(LOCF) TORO 1 + TORO 2 ENF + OB OB 100 71 P < 0.0001 Change from baseline 50 (cells/mm3) 35 0 24 Study week

  36. Significant improvement in general health, vitality, health distress and quality of life at week 24 (n= 965) OB ENF + OB * * * * * Energy / Fatigue General Health Health Distress Mental Health Summary Quality of Life *P < 0.05 Adjusted for treatment, stratum, treatment x stratum interaction, and baseline score Cohen et al. IAS, Paris 2003. Abstract 1148.

  37. Case #1 • 39 yo M HIV+ since 1994 Current 3 months ago 6 months ago CD4 175 200 240 VL 4.6 4.3 64.0 • Currently on ZDV/3TC/TDF/EFV • Previously exposed to 9 ARVs • Patient is adherent (>90%) • Resistance test • ddI, TDF (partial), SQV, APV, LPV/r susceptible

  38. Summary of Tenofovir DrugInteraction Data

  39. Current Single PI Regimens Dual PI Regimens With PK Enhancement High peak contribute to toxicity Low peak levels may reduce side effects Plasma drug levels High trough levels increase potency Drug required to block replication Low trough insufficient to completely block replication Two-drug Combination may increase potency Incomplete Suppression Leads to Resistance More Complete Suppression Increases Durability of Response Rational for Boosted or Dual PIs

  40. 1. Drugs such as RTV, rifampin, etc, bind to transcription regulator 2. Increased expression of gene of drug metabolizer 3. Increase in protein levels leading to induction of drug metabolism • CYP3A4 • CYP2D6 • GST • OATP • MDR1 (P-gp) Drug metabolizing gene XRE transcription regulator Xenobiotic response elements (XRE) – Modulators of drug metabolism • Clinical significance • Cell lines used to evaluate induction or inhibition of drug metabolism which lack XREs – not helpful in predicting drug metabolism • SQV may block the binding of RTV to XRE, preventing induction of CYP3A4 – may explain why SQV is boosted so potently by RTV Flexner CW, et al, 2nd IAS, Paris 2003, #126

  41. Induced by: RTV, NFV, EFV, NVP Inhibited by: RTV, NFV, IDV, APV, SQV, DLV Inhibited by: RTV Induced by: RTV, NFV Inhibited by: EFV, DLV Induced by: RTV, NFV Inhibited by: DLV Induced by: RTV, NFV ? Induced by: EFV, NVP Effect of Antiretroviralson Drug Metabolism 3A4 2C19 2D6 2C9 1A2 2E1 2A6 2B6 2C8

  42. Interaction BetweenLPV/r and APV Dosage (mg BID) LPV Level APV Level Ref APV LPV/RTV 600 400/100  50%  50% 1 600* 400/100*  40-60%  2 600 or 750 400/100   51% 3 600 400/100  40%  40% 4 600 400/100   37% 5 *Also received nevirapine 1. Mauss S et al. AIDS 2002, 296–297; 2. Fätkenheuer G et al. AIDS 2001,15:2334–2335; 3. Solas C et al. 9th CROI, Seattle, 2002, #440; 4. Raguin G et al. ibid #420; 5. Baldini F et al. ibid, #423

  43. Trials of SQV/LPV/r 1000/400/100 mg BID in PI-experienced Cohorts Cohort Efficacy n Ruiz 24 36% <80 copies/ml at24 wk Hellinger 28 42% <50 copies/ml at24 wk Smith 36 61% >0.8 log10at 4 wk Zala 23 40% <500 copies/ml at 48 wk Staszewski 42 median HIV-RNA60 copies/mlat 24 wk 1. Ruiz et al. 9th CROI, 2002; poster 421-W; 2. Hellinger et al. 9th CROI, 2002; poster 451-W; 3. Smith et al. XIV IAC, 2002; poster TuPeB4547; 4. Zala et al. XIV IAC, 2002; poster TuPeB4492; 5. Staszewski et al. ICCAC, 2002; poster H-176

  44. n 19 23 42 Age (median yrs) 38.7 36.4 37.4 Male 13/19 (68%) 21/23 (91%) 34/42 (81%) Prior AIDS 14/19 (74%) 13/23 (57%) 27/42 (64%) NADIR CD4 count (median) 27 cells/mm3 40 cells/mm3 39.5 cells/mm3 Baseline CD4 count (median) 90 cells/mm3 96 cells/mm3 93 cells/mm3 Baseline pVL(median) 307,000 (5.49) 402,000 (5.60) 358,125 (5.55) LPV/r Plus Either SQV or APV BaselineCharacteristics APV SQV Total Zala et al. 14th IAC, Barcelona, 2002. Poster TuPeB4492

  45. SQV/RTV atorvastatin  347% AUC simvastatin  3059% AUC pravastatin  50% AUC AIDS 2002; 16: 569-577 NFV atorvastatin  74% AUC simvastatin  505% AUC Antimicrob Agents Chemother 2001; 45: 3445-3450 LPV/r atorvastatin  588% AUC pravastatin  30% AUC 40th ICAAC 2000; abstract 1644 fibrates fluvastatin pravastatin rosuvastatin statin-fibrates atorvastatin lovastatin simvastatin Lipid Lowering Agents and Protease Inhibitors Low interaction potential Use cautiously Contraindicated

  46. Case #2 • 53 yo M HIV+ since 1990 • CD4 14 cells/mm3 and HIV-RNA 5.3 log10 copies/ml • Currently on ABC, 3TC, APV, IDV/r • Previously exposed to everything but ddC

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