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Calvin Cohen, MD Harvard Medical School CRI New England Boston, MA

Calvin Cohen, MD Harvard Medical School CRI New England Boston, MA. Reexamining the Concept of Stable Therapy: When Should ART Be Adjusted?. Modifying Virologically Suppressive Therapy. First: do no harm Maintain virologic control Maintain CD4 responses

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Calvin Cohen, MD Harvard Medical School CRI New England Boston, MA

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  1. Calvin Cohen, MD Harvard Medical School CRI New England Boston, MA Reexamining the Concept of Stable Therapy: When Should ART Be Adjusted?

  2. Modifying Virologically Suppressive Therapy First: do no harm Maintain virologic control Maintain CD4 responses Second: address shortcomings of existing regimen Simplification: fewer pills, less frequent dosing Substitutions: address long-term toxicity issues associated with some antiretrovirals when better alternatives exist

  3. DHHS 2006 Initial Treatment: “Preferred” Components NNRTI Option EFV* OR PI Options Atazanavir (ATV) + ritonavir (RTV) Fosamprenavir (FPV) + RTV (bid) Lopinavir/ritonavir (LPV/RTV) (bid) NRTI Options Tenofovir (TDF) + emtricitabine (FTC)† ZDV + 3TC† *Avoid in pregnant women and women with significant pregnancy potential. †Emtricitabine can be used in place of lamivudine and vice versa. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 2006.

  4. 2006 Initial Antiretroviral (ARV) Regimens:International AIDS Society-USA Treatment Guidelines ABC, abacavir; r, boosted with RTV; SQV, saquinavir. *In selected patients;†Triple-NRTI regimens are no longer recommended as initial therapy because of insufficient antiretroviral potency compared with a regimen containing efavirenz. However, for patients requiring treatment with regimens that preclude use of NNRTIs or protease inhibitors, a combination consisting of zidovudine, abacavir, and lamivudine may be considered. Adapted from Hammer S et al. JAMA. 2006;296:827-843.

  5. 2008 Updated Treatment Guidelines: Recommended Initial NRTI Backbones for ARV-Naïve Adults ATV/r FPV/r LPV/r SQV/r TDF/FTC ABC/3TC EFV DRV/r or + TDF/FTC ABC/3TC JAMA. 2008;300(5):555-570.

  6. ACTG 5142: Lipoatrophy at 96 Weeks (n=50) 6 (n=73) 16 (n=43) 33 (n=67) 12 (n=63) 40 (n=41) 51 Lipoatrophy defined as >20% limb fat loss by DEXA scan TDF LPV ZDV d4T TDF EFV ZDV d4T 0 20 40 60 80 100 Percent patients with lipoatrophy DEXA, dual energy x-ray absorptiometry. Haubrich R et al. 14th CROI; 2007; Los Angeles. Abstract 38.

  7. RAVE: Median Change in Limb FatDEXA Arm Fat + Total Leg Fat in Grams (ITT M=F Analysis) P <.01, baseline to week 48 P=NS, between arms Moyle G et al. AIDS. 2006; 20:2043-2050.

  8. SWEET: Study Design Undetectable viral load (≤ 50 copies/mL) at screening Adequate baseline renal function (CrCl ≥ 60 mL/min) and hepatic (AST/ALT ≤ 5 x ULN) function. HBsAg negative No known resistance to TDF, FTC, ZDV, 3TC, or EFV 48 weeks Stable ZDV/3TC + EFV ≥ 6 months (N = 250) Randomized 1:1 DEXA substudy (N = 100) SWEET = Simplification With Easier Emtricitabine and Tenofovir . CrCl, creatinine clearance; ULN, upper limit of normal. Fisher M et al. 11th EACS; 2007; Madrid. Abstract PS5/7.

  9. SWEET: Percentage <50 c/mL (ITT) at Week 48 88% 85% P = .70 % Patients with HIV RNA < 50 c/mL Time Virological failure*: TDF/FTC 0/116 (0%), ZDV/3TC 1/116 (<1%) *Virological failure = Subjects with 2 consecutive postbaseline value ≥ 400 copies/mL. Fisher M et al. 11th EACS; 2007; Madrid. Abstract PS5/7.

  10. SWEET: Effect of Previous ZDV Exposure on Total Limb Fat Change From Baseline at Week 48 by Years of Previous Exposure to ZDV P = .014 TDF/FTC P = .13 0.4 0.3 0.2 0.1 0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 P = .99 ZDV/3TC P = .37 P = .53 n=20 5.41* n=18 n=16 n=20 Median Change in Limb Fat (kg) 6.20* 3.68* 4.01* P = .053 <3 Years ≥3 Years Years on ZDV DEXA substudy treated analysis set and subset of whole body fat composition *Median baseline limb fat Moyle G et al. 15th CROI; 2008; Boston. Abstract 938.

  11. D:A:D Study: Recent but Not Past Use of ABC or ddI Predicted Risk of MI Rates of MI Suggests drug effect is reversible upon cessation of drugs *Recent = still using or stopped within last 6 months; †Past = last used more than 6 months ago. D:A:D Study Group. Lancet. 2008;371(9622):1417-1426.

  12. D:A:D Study: Increased Risk of MI Associated with Recent ABC or ddI Use Remained After Additional Adjustment Association With Recent* Didanosine Use Association With Recent* Abacavir Use 1.49 1.90 • No further adjustment† • Adjustment also for: • Latest CD4 • Latest HIV RNA • Latest Lipids • Latest blood pressure • Diabetes • Fat loss/gain • Latest glucose 0.5 1 1.5 2 2.5 3 0.5 1 1.5 2 2.5 3 Adjusted Relative Rate (95% CI) Adjusted Relative Rate (95% CI) *Recent = still using or stopped within last 6 months. †All data depicted are also adjusted for demographic factors, calendar year, cohort, CV risk factors that are unlikely to be modified strongly by ART use, and cumulative exposure to other antiretroviral drugs. D:A:D Study Group. Lancet. 2008;371(9622):1417-1426.

  13. SMART Study: Hazard Ratios for Four Types of CVD While Patient Receiving ABC vs Using “Other NRTIs” or TDF 1.5 8.9 70.4 2.2 1.6 ◄ Favors ABC Favors “Other” / TDF 1.8 CVD, major ‏ 4.3 13 Clinical MI 2.7 CVD, minor 1.9 CVD, expanded def. 0.1 1 10 ABC compared to “other NRTIs” Hazard ratio (95% CI) of CVD ABC compared to TDF Adapted from: Lundgren J et al. XVII IAC; 2008; Mexico City. Abstract THAB0305.; SMART/INSIGHT, D:A:D Study Groups, AIDS. 2008;22:F17-F24.

  14. GSK: Analysis of ABC Studies From 1995 to 2006 CV Outcomes With No Exposure to ABC Compared With Exposure to ABC Cutrell A et al. XVII IAC; 2008; Mexico City. Abstract WEAB0106.

  15. ACTG 5202: Targeted Events *One subject in ABC/3TC arm died, possibly as result of drug hypersensitivity reaction (HSR) after rechallenge Sax PE,et al. XVII IAC; 2008; Mexico City. Abstract THAB0303.

  16. TDF vs ZDV / d4T: Change in renal labs to wk 144 on TDF: Subset – BL mild renal impairment* • a. Median (IQR) values • P value is for comparison of the TDF and control distributions (Wilcoxon rank sum test) *Glomerular filtration rate (GFR) 50-80 mL/min by Cockroft-Gault (CG) Gallant JE et al. 11tth EACS; 2007; Madrid. Poster P9.7/05.

  17. Retrospective Chart Review: Assessment of Nephrotoxicity Risk With TDF Retrospective study to assess incidence and risk factors for nephrotoxicity on TDF Definition: Decrease in CrCl by ≥25 mL/min or GFR by >50% Nephrotoxicity risk similar between TDF-exposed (4.7%) and TDF-unexposed patients (4.2%) Factors associated with nephrotoxicity on TDF: NSAID, nonsteroidal anti-inflammatory drug Castellano C et al. XVII IAC; 2008; Mexico City. Abstract WEAB0104.

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