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Management of Late “Virologic Failure” and Viral Fitness

Management of Late “Virologic Failure” and Viral Fitness. Steven G. Deeks, MD. SG Deeks, MD. Presented at IAS –USA /RWCA Clinical Conference, August 2004. The International AIDS Society–USA. Slide # 2. Why not Switch?. TORO

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Management of Late “Virologic Failure” and Viral Fitness

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  1. Management of Late “Virologic Failure” and Viral Fitness Steven G. Deeks, MD SG Deeks, MD.Presented at IAS–USA/RWCA Clinical Conference, August 2004. The International AIDS Society–USA

  2. Slide #2 Why not Switch? TORO 995 three-class experienced subjects randomized to optimized back-ground (OB) vs. enfuvirtide (T20) plus OB P<0.0001 % < 400 copies/mL 30% 12% OB + T20 OB SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  3. Slide #3 When To Switch: Who Does Well and Who Does Not? Montaner J, et al. 2nd IAS, Paris 2003, #116 SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  4. Slide #4 When to Switch in Patients with MDR:The Clinical Dilemma • Enfuvirtide — or any potentially effective drug — should be deferred until at least two additional effective agents are available • Therapy should be modified before the development of advanced immunodeficiency and before the development of high-level resistance to existing drugs SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  5. When will patients with MDR and limited options have at least 2 effective agents?The question is when to switch, not how to switch Slide #5 SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  6. Slide #6 Tipranavir/ritonavir in “deep salvage” Amprenavir/r (n=74) Saquinavir/r (n74) Lopinavir/r (n=78) HIV RNA (log10 copies) Tipranavir/r (n=66) Curry K, et al. 5th International Workshop on Clinical Pharmacology of HIV Therapy; April 1-3, 2004; Rome, Italy Median CD4+ T cell count 140, viral load 5.0 log SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  7. CCR5 CXCR4 Y D M Q I Y S - NH 2 V T I M - NH S S G E 2 D S N P Y Y N Y D T S I M I D Y S Y K T D E E G E K Q N * N S G L P C E I Q P Q Y G M F G C C S Q S C I E K W F I Y F S R * D L E P K E N N W F E D F F S P V F V W G F Y L N N E W G Y V Q N H E K N G E N F L F N A N V D A A T Q Q S L K R A Q R I T F E F N D A M S I H Q F L V V L Q F D S F A T R D N H A C C A Y S T * C L A C F V S K Q Y 277- T K Q I -282 R Y R K N 31- 102- Q -89 -168 -197 -258 I D K D 110- N A -97 39- -176 -202 -262 L F W L P L H T I L M P L A A H I I F Q P A L F V L V T A V I S I S F Y L F W G T I I L I V L T V Y I W H F I V M G I T F S P L G G I T E I S P G I A G D L T V F Y L P L Y N L V V I I T L T Y I P I L Y Y L F L S L P M G I F I V T L P F A F I F L G F A L P W A T F T L V L N L L G P W L F F G F F V L F C H G L Y L I C C H F D L G S A M V F L C V I D L S S P A I V F A C V V G S I V Y N I G A V L F N L V I M N A I F F T C I I V P S G N I L V C S L A P V W W L L I I Y M I I L L L G Y I L I I V L H F A Y I C I L Y I L N L I S V G S T I Y V V L R I V I V F A L L T I F F A L M V Y S I T T L L V L I Y I T L L I V V G A G I E G Y K K D K S N I D K R -65 75- -133 154- 224- -239 67- 219- V -57 -125 146- -235 K K 308- Q 303- L E R Q K L R G T V A D H C D L V F A A F S Y F F A Y L A Y L K T K T K T R N L L L F K S T R K M L L R M T L L Q A R S G R L S H R S V H S K A R K A S V R K S I K H F I K L S R T C K Q V C G H R K R V K K N H V R G R P E K K A I T G R K H Q N S A Q Q A L G S K C F E V F A L A H C I S P S S S E S S E S S F E R T V T R T Y S A S H V S G S -352 S E Q E I S L V G - COOH 352 Slide #7 R5 viruses Macrophage-tropic Non-syncytium inducing Associated with slow progression (causality not clear) Prevalent in early disease Transmitted variants • X4 viruses • T-cell tropic • Syncytium-inducing • Associated with rapid progression • (causality not clear) • Emerge in late disease • R5: 62% (n=378) • X4: 4% (n=23) • Dual: 34% (n=211) TORO X4/R5 viruses: Mixtures vs. Dual Tropic SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  8. AIDS-Free Survival Years Slide #8 Co-receptor Tropism (X4/R5): Do X4 (“SI”) variants cause rapid disease progression? R5 Virus R5/X4 or X4 Virus 207 HIV-infected hemophiliacs (age 6-19) enrolled in the HGDS natural history cohort, 1989-1990 SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  9. Can partially effective drugs (or drug classes) become “fully” effective by increasing exposure? Slide #9 SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  10. Slide #10 Abbott 049: Steady-State Lopinavir Mean (SD) Concentrations Flexner C, et al., Poster# 843, 2nd IAS Conf, Paris, July 2003 SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  11. Slide #11 Abbott 049: Predictors of a viral load < 400 (week 48) Predictor Unadjusted Adjusted Baseline VL 0.01 NS Fold change IC50 0.02 NS Number of LPV mutations 0.04 NS Active NRTIs 0.02 0.04 LPV IQ 0.002 0.007 SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  12. What about “dual boosted protease inhibitors”? Slide #12 SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  13. Tipranavir BI 1182.51: Controlled study of Dual Boosted PIs Slide #13 RCT (n=296) ≥3 mutations at protease codons 33, 82, 84, 90 LPV/r + OBR (400 mg/100 mg) APV/r + OBR (600 mg/100 mg) SQV/r + OBR (1000 mg/100 mg) TPV/r + OBR (500 mg/200 mg) TPV/r 500/100 mg added at 2 weeks Final RTV dose 200 bid in all arms SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  14. Slide #14 Dual boosted PI therapy vs. RTV/TPV in “deep salvage” Monotherapy TPV added to LPV/APV/SQV HIV RNA (log10 copies) SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  15. Why not switch? • Salvage regimens are often complex, with significant short-term and long-term complications • Risk may outweigh benefit in elderly or patients with advanced co-morbid conditions (renal, liver disease) • Patients are often doing well (or are progressing slowly) • Costs of treatment • Aggressive switch strategies risk future therapeutic options

  16. Slide #16 PLATO: Steady State Viremia and Rate of CD4+ Cell Decline CD4 Slope (cells/year) Steady State Viral Load (copies/mL) SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  17. Slide #17 Resistance Replicative Capacity Viremia HIV may be constrained in its ability to become highly resistant and highly fit, thus resulting in durable partial suppression J Virology 2002; 76:11104-12 SG Deeks, MD. Presented at IAS–USA/RWCA Clinical Conference, August 2004.

  18. Summary: Pathogenesis of Drug-Resistant HIV Despite emergence of drug-resistance, plasma HIV RNA levels often remain below the off-treatment set-point as long as treatment is maintained • Persistent antiviral activity against resistant variant • Reduced viral fitness (replicative capacity) • Enhanced HIV specific immune responses • Rate of CD4+ T cell decline delayed in presence of MDR compared to WT • • Predicted by “delta VL” ( > 0.7 log?) • • Predicted by a steady-state viral load < 10 to 30K • • Mediated by reduced T cell activation

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