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Managing Antiretroviral Therapy in Treatment-Experienced Patients: Multiple Regimen Failures

Managing Antiretroviral Therapy in Treatment-Experienced Patients: Multiple Regimen Failures. MATEC Catherine Creticos, M.D. Medical Director. Case Study 1.

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Managing Antiretroviral Therapy in Treatment-Experienced Patients: Multiple Regimen Failures

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  1. Managing Antiretroviral Therapy in Treatment-Experienced Patients: Multiple Regimen Failures MATEC Catherine Creticos, M.D. Medical Director

  2. Case Study 1 • D.R. is a 42 yo male HIV+ for 12 years on multiple HIV treatment regimens, starting with Combivir (ZDV/3TC) in the mid-1990s & including Crixivan (IDV) and Lexiva (APV). Most recently he has been on a combination of Trizivir (ZDV/3TC/ABC), Videx (DDI), and boosted Reyataz (ATV/r). His viral load = 33,000 and CD4 = 355.

  3. Case Study 2 • S.F. is a 31 yo female HIV+ for past 10 yrs. She has been on ARV therapies but non-adherent. Her CD4 is repeatedly <100. At her most recent visit she was on Epzicom (3TC/ABC), Invirase (SQV), & Kaletra (LPV/r). Labs show her viral load = 55,600 and CD4 = 73. She returns to discuss changing her therapy and tells you that she is again off her ART for the past 2 weeks.

  4. DHHS and IAS-USA Guidelines: Goals of Therapy • Evolving goal of antiretroviral therapy for all HIV-positive patients regardless of the extent of previous treatment experience • Achieve and maintain undetectable VL • Now applies to an increasing number of treatment-experienced patients Hammer SM, et al. JAMA. 2006;296:827-843. DHHS guidelines, May 2006. Available at: http://aidsinfo.nih.gov.

  5. Goals of Therapy in PatientsWith Access to < 2 Active Agents • Reduce VL by ≥ 1 log10 • Stabilize CD4 count • Minimize drug toxicity • Prevent clinical progression and death • Avoid new resistance mutations that could reduce future options • Avoid “monotherapy” with new drugs

  6. RESIST: Phase 3 Study of Boosted Tipranavir (TPV/r) Patients failing PI-containing HAART VL > 1000 Any CD4+ HIV resistance expert panel Best PI choice TPV/r arm Computerizedrandomization to OBR plus: Preselection of regimenby investigator: CPI + OBR †(± enfuvirtide) Baseline genotypic resistance testing* CPI arm LPV/r, IDV/r, SQV/r, APV/r †CPI, comparator PI OBR, optimized background Failures in CPI arm after Wk 8 eligible for TPV/r in rollover study • * Entry criteria: • ≥ 1 primary PI mutation: 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M • ≤2 mutations: 33, 82, 84, or 90 Farthing C, et al. ICAAC 2006. Abstract H-1385. Hicks CB, et al. Lancet. 2006;368:466-475.

  7. RESIST: VL<50 copies/mL at wk 96 100 TPV/r(n = 746) CPI/r (n = 737) 80 ITT: NC = F 60 Patients With HIV-1 RNA< 50 copies/mL (%) P < .0005 40 22.8% 20.4% 20 9.1% 10.2% 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Farthing C, et al. ICAAC 2006. Abstract H-1385.

  8. RESIST 1 and 2: TPV/r Results at 96 wks TPV/r similar toxicity profile to comparator PIs at wk 48, except: • Grade 3/4 ALT (10.1% vs 3.3%), AST (6.3% vs 2.9%) • Grade 3/4 TGs (30.8% vs 23.1%), TC (4.3% vs 0.7%) (p < .0001 for all comparisons) 100 100 TPV/r Control TPV/r Control 80 80 p < .0001 p < .0002 60 60 p < .0001 44.4 Patients With VL < 400 copies/mL (%) Patients With VL < 50 copies/mL (%) p < .0005 34.7 40 40 26.9 20.4 14.4 14.4 20 20 9.1 10.9 n =746 n =746 0 0 All Patients First-Time ENF Use All Patients First-Time ENF Use Farthing C, et al. ICAAC 2006. Abstract H-1385. Hicks CB, et al. Lancet. 2006;368:466-475.

  9. RESIST: Greater Response at wk 24 With More Active Agents in OBR 100 TPV/r CPI/r 80 60 54.7 Patients With  1 log10 Reductionin VL (%) Week 24 46.2 41.2 37.4 34.3 40 19.9 18.9 13.1 20 12.9 9.1 0 0 1 2  3 Overall Number of Sensitive Background ARVs Cooper D, et al. CROI 2005. Abstract 560.

  10. 14.7-52.5 Median FC: 0.7-0.9 1.1-1.4 2.0-3.1 3.3-3.9 Relationship of TPV Score to TPV Phenotype Results and Response TPV Score* 0-1 2-3 4-5 6-7 8-9 0 -0.08 (n = 4) -0.45 (n = 260) -0.49 (n = 68) -1 -0.89 (n = 242) Median Change in VL at Wk 24* (log10 copies/mL) Distribution of patients in RESIST-1 & -2 by BL TPV score -2 -2.10 (n = 144) -3 *10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V Valdez H, et al. Resistance Workshop 2005. Abstract 27.

  11. L K L D V L M M I G I F I L A C V V I N L 10 20 24 30 32 33 36 46 47 48 50 53 54 63 71 73 77 82 84 88 90 F R I N I I I I V V L L V p V C I A V D M I M F L L A V L T S F S R I V V A T T V M A S C S TPV Mutation Score vs IAS-USA Protease Gene Resistance Mutations L I K L E M K M I I Q H T V N I TPV Score 10 13 20 33 35 36 43 46 47 54 58 69 74 82 83 84 V V M F G I T L V A E K P L D V R M T V V IAS-USA • Many mutations (13, 35, 43, 58, 74, 83) have not been associated with resistance to other PIs • Major mutations (D30N, G48V, N88D, L90M) associated with other PIs do not contribute to Tipranavir (TPV) mutation score Kohlbrenner VM et al. HIV-DART 2004. Abstract 40.

  12. Adverse Effects of Boosted Tipranavir: Black Box Warnings TPV/r associated with reports of • Fatal and nonfatal hepatitis and hepatic decompensation • More hepatotoxicity in patients on TPV/r in RESIST 1 and 2; patients with chronic HBV or HCV coinfection have increased risk • Fatal and nonfatal intracranial hemorrhage • 13 patients receiving TPV/r experienced intracranial hemorrhage; use with caution in patients at risk of increased bleeding from trauma, surgery, or other medical conditions, or those receiving medications known to increase risk of bleeding Aptivus [package insert]. Ridgefield, Conn: Boehringer Ingelheim; June 2006.

  13. POWER 1 and 2: BoostedDarunavir (DVR) Study Design Investigator-selected CPI(s) + OBR • DRV/r 600/100 mg BID provided greatest virologic response in Wk 24 analysis; FDA-approved dose for treatment-experienced pts DRV/r 400/100 mg QD + OBR • PI-, NRTI- and NNRTI-experienced • 1 PI mutation (IAS-USA) • PI-based regimen • VL > 1000 copies/mL Investigator-selected CPI(s) + OBR (without NNRTIs) DRV/r 800/100 mg QD + OBR DRV/r 400/100 mg BID + OBR DRV/r 600/100 mg BID + OBR VL, viral load; OBR, optimized background regimen (NRTIs ± enfuvirtide) Lazzarin A, et al. IAC 2006. Abstract TUAB0104.

  14. POWER 1 and 2: VL<50 at wk 48 (ITT-TLOVR) 100 DRV/r 600/100 mg BID *P < .001 vs comparator PI/r. 80 Control 45* 46* 60 Patients With VL< 50 c/mL (%) 40 12 10 20 0 0 1 2 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit. Lazzarin A, et al. IAC 2006. Abstract TUAB0104.

  15. 58 n = 36 11 n = 35 POWER 1 and 2: VL<50 at wk 48 by Baseline Group 46 n = 110 Overall 10 n = 120 ENF Used(Naive) 44 ENF NotUsed n = 61 10 n = 70 DRV/r 600/100 BID 44 n = 55 ≥ 3 PrimaryPI Mut 5 CPI/r n = 74 20 No Sensitive ARVs in OBR n = 25 0 n = 18 54 n = 44 ≥ 1 Active Agent in OBR 11 n = 11 0 20 40 60 80 100 Patients With VL < 50 copies/mL at wk 48 (ITT, NC = F) (%) Lazzarin A, et al. IAC 2006. Abstract TUAB0104.

  16. POWER 3: VL<50 at wk 24 by ITT-TLOVR • POWER 3: ongoing phase III open-label study, DRV/r 600/100 mg[1] • Safety analysis similar to POWER 1 and 2[2] 70 POWER 1 (n = 65) 60 POWER 2 (n = 66) 53 50 POWER 3 (n = 327) 40 40 Patients With VL < 50 copies/mL (%) 39 30 20 10 0 B/L 2 4 8 12 16 20 24 Weeks 1. Molina JM, et al. IAC 2006. Abstract TUPE0060. 2. Madruga V, et al. IAC 2006. Abstract TUPE0062.

  17. Baseline fold-change to DRV (by Antivirogram) was strong predictor of Week 24 response in POWER 1, 2, and 3 Effect of Baseline Darunavir Fold-Change on Response to Darunavir 100 Distribution of pts by baseline DRV FC 80 60 50 Patients With VL < 50 copies/mL at Wk 24 (%) 40 25 13 20 n = 255 65 48 0 FC ≤ 10 FC 11-40 FC > 40 Baseline DRV FC DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.

  18. Effect of Baseline DRV-associated Mutations on Response to DRV • 11 PI mutations associated with reduced response • V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V 100 Distribution of pts by baseline # of DRV mutations 80 64 60 50 Patients With VL < 50 copies/mL at Wk 24 (%) 42 40 22 20 10 n = 67 94 113 58 41 0 0 1 2 3 ≥ 4 Baseline No. of DRV Mutations DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.

  19. 18% n = 11 12% n = 17 59% n = 17 15% n = 33 POWER 1, 2, and 3: Effect of Fuzeon (ENF) by Baseline Fold Change to Darunavir (ITT-TLOVR) Response (< 50 c/mL) Adjusted estimate Controlling for # of active NRTIs in OBR, # of primary PI mutations, DRV FC, and ENF use (naive/not used) N (%)* 28 (9%) FC > 40 FC 10-40 50 (17%) 49% 53% n = 64 FC  10 P = .32 223 (74%) 39% 52% n = 159 0 20 40 60 80 100 *Patients reaching Wk 24 or D/C earlier, excluding those who had previously used ENF Subjects using ENF naively Subjects not using ENF Data on file. Tibotec Therapeutics. 2006

  20. Relationship Between Activity of OBR and Response to DRV/r 600/100 mg • Subgroup analyses of pooled POWER 1, 2, and 3 data • Highest rates of VL<50 in pts with ≥ 2 active agents in OBR[1] • No incremental benefit of active ENF if ≥ 1 active NRTI in OBR[1] • Phenotypic susceptibility score (PSS) of OBR also predicted VL < 50 at Wk 24[2] • PSS ≤ 0.5: 34% • PSS 0.5-1.5: 49% • PSS > 1.5: 52% 1. Pozniak A, et al. BHIVA, 2006. Abstract P3. 2. Vangeneugden T, et al. Resistance Workshop, 2006. Abstract 1138.

  21. FDA Indications for New PIs Boosted Tipranavir (TPV/r) • “Adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple PIs” Boosted Darunavir (DRV/r) • “Antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor”

  22. Most Clinical Isolates Are Maximally Susceptible to Both TPV and DRV • Analysis of 56,018 samples submitted for routine resistance testing DRV 0.2% 1.5% TPV 5.0% 8.7% Susceptibility Maximal Reduced Minimal 94.8% 89.8% Picchio G, et al. ICAAC 2006. H-999.

  23. Tipranavir and DarunavirMutations and Phenotypic Cutoffs Similarities and Differences in Key Mutations Phenotypic Cutoffs 1. Oakley E, et al. Resistance Wkshp 2006. Abstract 71. 2. Bacheler L, et al. Euro Resistance Wkshp 2006. Abstract 40. 3. De Meyer S, et al. Resistance Wkshp 2006. Abstract 73. 4. Winters B, et al. Resistance Wkshp 2006. Abstract 160.

  24. Susceptibility to Tipranavir or Darunavir After Failure of Each Other Limited data suggest both agents may retain activity after failure of the other • Among 39 patients with virologic rebound on DRV/r[1]; median 8.14 fold-change loss of DRV susceptibility from baseline; however, no decrease in susceptibility to TPV • In POWER 3, 51 patients (11%) were failing TPV/r at entry[2];44% achieved VL<50 copies/mL at wk 24, similar to overall response to DRV/r in POWER 1, 2, and 3 (42%) 1. De Meyer S, et al. CROI 2006. Abstract 157. 2. Lefebvre E, et al. ICAAC 2006. Abstract H-1387.

  25. Key Steps to Regaining Virologic Suppression • Aim for undetectable viral load • Use cumulative results from current and prior resistance tests along with treatment history to assess drug susceptibility • Select a new regimen containing at least 2 fully active agents

  26. Use 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 cell 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 agents or use deferred until other new agents available

  27. What to Combine With the New PIs in Treatment-Experienced Patients • NNRTIs: most patients have resistance to first-generation NNRTIs at this stage • Assess NRTI resistance carefully, considering all resistance test results and treatment history • Other PIs: cannot be combined with tipranavir (TPV); limited data with darunavir (DRV); minimal data supporting dual-boosted PIs • Fuzeon (ENF): often the best choice in patients with extensive 3-class resistance • New agents

  28. Expanded Access Availability • Etravirine (TMC125): available since August 2006 • www.clinicaltrials.gov/ct/show/NCT00354627?order=2 • MK-0518: available since September 2006 • www.benchmrk.com/secure/earmrk/earmrk.html • Maraviroc: expected to be available Q1 2007

  29. Combining New Agents With the New PIs • Etravirine (TMC125): second-generation NNRTI • DUET study in progress (DRV ± ETV) • EAP available • Integrase inhibitors • MK-0518: EAP available, BID, no RTV boosting effect • Entry inhibitors • Maraviroc (MVC): CCR5 inhibitor, EAP available soon

  30. TMC 125-C223: Response to Etravirine (ETV) at wk 48 • 199 patients w/NNRTI resistance and ≥ 3 primary PI mutations • Median NNRTI Fold Change • NVP: 61.3 • EFV: 41.4 • ETV: 1.6 • Randomized to • ETV (400mg or 800mg BID) + NRTIs ± LPV/r ± ENF • Active control: best available regimen from approved agents (NNRTIs excluded) 100 80 60 VL < 50 copies/mL at Wk 48 (%) 40 23 22 20 0 0 ETV400mg BID ETV800mg BID Control Cohen C, et al. IAC 2006. Abstract TUPE0061.

  31. Each of the following mutations, always in combination with up to 4 other mutations was associated with a mean Fold Change > 10 K101P, V179E, V179F, Y181I, Y181V, G190S, M230L For 179E, G190S, or M230L, the additional mutations always included Y181C when FC > 10 TMC 125-C223: Baseline NNRTI Mutations and Response at wk 48 Response to ETV 800 BID by # of B/L NNRTI mutations ETV800 BID ActiveControl 0* 1 2 ≥ 3 0 n = 79 n = 40 n = 14 n = 19 n = 16 n = 30 -0.14 -0.5 -0.54 -1.0 Mean Change in VL Log10 -0.9 -1.01 -1.5 -1.38 -1.67 -2.0 *All patients had confirmed NNRTI mutations from prior genotypic resistance tests ITT, NC = no change from baseline Cohen C, et al. IAC 2006. Abstract TUPE0061.

  32. Pilot Data on DRV/r Plus Etravirine • Combination DRV+ETV associated with 30%  in ETV levels vs controls; not judged to be clinically significant[1] • 3-class resistant patients treated with DRV/r 600/100mg BID + ETV 200mg BID + NRTIs ± ENF • Montaner et al.[2] • 4/5 patients achieved VL < 50 copies/mL at wks 20-24 • Boffito et al.[3] • 10/12 patients completed 24 weeks of therapy • 9/10 achieved VL<50, 1/10 = 722 copies/mL • Median VL decline, -2.7 log10; CD4 increase: 113 cells/mm3 • No serious adverse events or changes in laboratory safety 1. Boffito M, et al. CROI 2006. Abstract 575c. 2. Montaner J, et al. IAC 2006. Abstract THPE0136. 3. Boffito M, et al. ICAAC 2006. Abstract H-1000.

  33. Raltegravir (MK-0518):Integrase Inhibitor BENCHMRK Trials • BENCHMRK-1 and -2: parallel randomized, double-blind, placebo-controlled phase III studies BENCHMRK-1 and -2 designed to evaluate efficacy and safety of raltegravir + OBR in triple-class–resistant patients • Raltegravir (MK-0518) with optimized background regimen [OBR] demonstrated superior virologic efficacy vs placebo at wk 16 in patients with triple-class resistance • Safety and tolerability of raltegravir appeared comparable to placebo Cooper D, et al CROI 2007, Abstracts 105aLB Steigbigel R, et al CROI 2007, Abstract 105bLB

  34. Raltegravir (MK-0518): Virologic Suppression Through Week 24 (NC=F) MK-0518 200 mg BID (n = 43) MK-0518 600 mg BID (n = 45) MK-0518 400 mg BID (n = 45) OBR alone (n = 45) 100 100 80 80 60 60 Patients With VL < 50 copies/mL (%) Patients With VL < 400 copies/mL (%) 40 40 20 20 0 0 2 4 8 12 16 24 0 2 4 8 12 16 24 Week Week Grinsztejn B, et al. ICAAC 2006. Abstract H-1670b.

  35. Maraviroc (MVC) CCR5 Inhibitor: MOTIVATE Trials • Randomized, double-blind, placebo-controlled, phase IIb/III clinical studies: Maraviroc + Optimized Background Therapy in Viremic, ART-Experienced Patients (MOTIVATE) 1 and 2 • Maraviroc plus optimized background therapy [OBT] • MVC associated with significantly greater viral suppression than placebo • Similar activity in MVC once-daily and twice-daily arms • In combined analysis, higher rate of viral suppression with twice-daily MVC in patients with no active drugs in OBT Lalezari J, et al CROI 2007 Abstract 104bLB Nelson M, et al CROI 2007 Abstract 104aLB

  36. Maraviroc (MVC) CCR5 Inhibitor: MOTIVATE Trials (cont.) • Maraviroc plus OBT associated with significantly greater CD4 cell count increase vs placebo • Among patients with tx failure, MVC recipients more likely to exhibit shift in detected tropism to X4 or dual/mixed-tropic R5/X4 • Fewer patients receiving MVC experienced tx failure compared with those receiving placebo • Safety profiles similar between MVC & placebo Lalezari J, et al CROI 2007 Abstract 104bLB Nelson M, et al CROI 2007 Abstract 104aLB

  37. MVC Safe in Experienced Patients With Detectable X4 HIV • No difference in mean VL ↓ between MVC + OBR vs placebo + OBR • -0.97, -0.91, -1.20 log10 for placebo, MVC QD, and MVC BID at wk 24 • No major AEs; no hepatotoxicity, lymphoma, or adenocarcinoma • Higher CD4+ cell counts at wk 24 with MVC vs placebo • Detection of only X4-tropic HIV more common at tx failure with MVC vs placebo; however, similar CD4 cell count increases in pts with detection of only X4 virus vs overall MVC-treated population, suggesting no impact on immunologic recovery Mayer H, et al. IAC 2006. Abstract THLB0215.

  38. Other New Agents in Advanced Clinical Trials • Integrase inhibitor • GS-9137: QD, boosted by RTV • Maturation inhibitor • Bevirimat (PA-457) • Entry inhibitors • Vicriviroc: CCR5 inhibitor

  39. Guidelines for Choosing a Nonsuppressive “Holding Regimen” • Do not use an NNRTI if resistant • NNRTI mutations have no beneficial impact on fitness • Accumulation of additional mutations may result in cross-resistance to second generation NNRTIs • Use Epivir (3TC) or Emtriva (FTC) even if resistant • Simple and well-tolerated drugs • M184V  fitness, increases activity of ZDV, D4T, TDF • Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations

  40. Estimated Timeline for Availability of New Antiretrovirals CXCR4 inhibitors Entry inhibitors (anti-gp120, CCR5) GS-9137 Maturation inhibitors Vicriviroc Integrase inhibitors Maraviroc TNX-355 Bevirimat MK-0518 TMC278 Etravirine PIs Brecanavir NNRTI Apricitabine NRTI

  41. Case Study 1 • D.R. is a 42 yo male HIV+ for 12 years on multiple HIV treatment regimens, starting with Combivir (ZDV/3TC) in the mid-1990s & including Crixivan (IDV) and Lexiva (APV). Most recently he has been on a combination of Trizivir (ZDV/3TC/ABC), Videx (DDI), and boosted Reyataz (ATV/r). His viral load = 33,000 and CD4 = 355.

  42. Case Study 1:Resistance Mutations • RT mutations: • M41L, E44D, D67N, V118I, M184V, L210W, T215Y • PR mutations: • L10I, K20I, M36I/M, M46I, I54V, L63P, G73T, A71T, I84V, L90M • Interpretation of Genotype (GT): • By Quest • Sensitive to all NNRTIs and TPV • Resistant to all NRTIs

  43. Major PI Mutations: M46I, I54V, I84V, L90M Minor PI Mutations: L10I, A71T, G73T Other Mutations: K20I, M36I, L63P Protease Inhibitors ATV: High-level resistance DRV: Intermediate resistance FPV: High-level resistance IDV: High-level resistance LPV: Intermediate resistance NFV: High-level resistance SQV: High-level resistance TPV: Intermediate resistance NRTI Mutations: M41L, E44D, D67N, V118I, M184V, L210W, T215Y NNRTI Mutations: None Nucleoside RTI 3TC: High-level resistance ABC: High-level resistance AZT: High-level resistance D4T: High-level resistance DDI: High-level resistance FTC: High-level resistance TDF: Intermediate resistance Non-Nucleoside RTI DLV: Susceptible EFV: Susceptible NVP: Susceptible Drug Resistance Interpretation Stanford Database Website

  44. Clinical Decisions and Questions • What about the lack of resistance to the NNRTIs? • Can an effective regimen be constructed for this patient? What if you think the regimen would be effective but not completely suppressive? • How do you feel about combining agents that have not been combined in clinical studies? • Would this patient benefit from drug interruption? • How do you deal with the discordance between interpretations? • What antiretroviral combinations would you consider for this patient?

  45. Case Study 2 • S.F. is a 31 yo female HIV+ for past 10 yrs. She has been on ARV therapies but non-adherent. Her CD4 is repeatedly <100. At her most recent visit she was on Epzicom (3TC/ABC), Invirase (SQV), & Kaletra (LPV/r). Labs show her viral load = 55,600 and CD4 = 73. She returns to discuss changing her therapy and tells you that she is again off her ART for the past 2 weeks.

  46. Case Study 2 • Do you obtain a resistance assay at this time? • What issues do you discuss at this visit?

  47. Case Study 2:Resistance Assays • RT mutations • M41L, l74V, Y115F, M184V, T215Y, Y181C • PR mutations • L10F, K20I, V32I, M46I, I47V, I54V, L63P, A71T, G73S, I84V, L90M

  48. Case Study 2:Resistance Assessment • By Quest Genotype (GT): • Sensitive to Viread (TDF), Sustiva (EFV), Tipranavir (TPV) • Partially sensitive to Zerit (D4T) • By Quest Phenotype (PT): • Sensitive to Zerit (D4T), Retrovir (ZDV), Viread (TDF); Sustiva (EFV); and Tipranavir (TPV) • Replication capacity: 5.5%

  49. Major PI Mutations: V32I, M46I, I47V, I54V, I84V, L90M Minor PI Mutations: L10F, A71T, G73S Other Mutations: K20I, L63P Protease Inhibitors ATV: High-level resistance DRV: High-level resistance FPV: High-level resistance IDV: High-level resistance LPV: High-level resistance NFV: High-level resistance SQV: High-level resistance TPV: High-level resistance NRTI Mutations: M41L, L74V, Y115F, M184V, T215Y NNRTI Mutations: Y181C Nucleoside RTI 3TC: High-level resistance ABC: High-level resistance AZT: Intermediate resistance D4T: Intermediate resistance DDI: High-level resistance FTC: High-level resistance TDF: Low-level resistance Non-Nucleoside RTI DLV: High-level resistance EFV: Low-level resistance NVP: High-level resistance Drug Resistance Interpretation Stanford Database Website

  50. Clinical Decisions and Questions • What are the risks and benefits of continuing the current regimen? • Is this patient a candidate for a treatment interruption? • What antiretrovirals would you possibly combine for this patient to construct an effective regimen? • What additional measures would you undertake in this patient’s HIV therapy?

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