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Antiretroviral Update Spring 2008 Lisa M. Chirch, M.D. Stony Brook University - CPHE NY/NJ AIDS Education and Training Center Objectives Review DHHS guidelines and most recent changes / additions Overview of recent significant clinical trial results Review currently approved, available antiretroviral (ARV) medications and known toxicities, idiosyncrasies Report on new agents in the pipeline, or under ongoing investigation in Phase II and III trials Case vignettes and discussion Indications for initiating ARV therapy for the chronically HIV-1 infected patient Clinical Category CD4+ cell count Recommendation AIDS-defining illness or severe symptoms* Any value Treat Asymptomatic CD4 <200/mm3 Treat Asymptomatic CD4 >200, <350 Treat Asymptomatic CD4 >350 Discuss risks and benefits, consider patient comorbidities and scenarios * Initiation of ARV also recommended for individuals co-infected with Hepatitis B, HIV-associated nephropathy, and pregnant women; Adapted from “Guidelines for the use of antiretroviral agents in HIV-1 – infected adults and adolescents,” U.S. Dept. of Health and Human Services. 2008. Predicted 6 month risk of AIDS according to age, CD4, and viral load Based on Poisson regression model: Phillips A, et al. AIDS 2004 (CASCADE CollaborationConcerted Action on SeroConversion to AIDS and Death in Europe: www.ctu.mrc.ac.uk/cascade Examples: 35 year old with CD4 100, has 6 month risk of progression to AIDS of 4.7% if viral load is 3,000; 9.3% if VL is 30,000; 18% if 300,000. 55 year old with CD4 of 150 has 4.7% risk if VL 3,000; 18.2% if VL 300,000. 55 year old with CD4 of 350 has 1.2% risk if VL 3,000, 3.6% if VL 100,000, 5% if VL 300,000. Which of the following fixed dose combinations (FDCs) are designated as preferred initial NRTI options according to the most recent DHHS guidelines? D ... an d )A B C/ 3 TC /3 T BC DV /A )Z C ZD ... an C TD an d C/ 3 )A B B )T DF /F T C TC an d ZD 20 ... V. .. 0% 0% 0% 0% A A) TDF/FTC and ZDV/3TC B) ABC/3TC and TDF/FTC C) ZDV/ABC/3TC and TDF/FTC D) ABC/3TC and ZDV/3TC Which of the following ARVs is contraindicated in women with CD4 cell counts above 250? A) Efavirenz B) Nelfinavir C) Nevirapine D) Didanosine 0% 0% si ne e an o D )D id ira )N ev B )N el fin a pi n z vi re n )E fa A 0% vi r 0% C 20 Which of the following regimens is not recommended in women who are or may become pregnant? A) EFV/TDF/FTC B) FPV/r plus ABC/3TC C) LPV/RTV plus ZDV/3TC D) All of the above ve ab o of th e D TV PV /R )L C )A ll pl us BC A lu s PV /r p )F B ZD ... C /3 T TC F/ F /T D )E FV A 20 0% 0% 0% 0% Preferred and Alternative ARVs in updated DHHS Guidelines Preferred Alternative NNRTI PI 2 NRTI Efavirenz Atazanavir +Ritonavir; Fosamprenavir + ritonavir (BID), lopinavir/ ritonavir (BID) Tenofovir/ Emtricitabine Nevirapine Atazanavir Fosamprenavir Fosamprenavir (QD) Lopinavir/ ritonavir (QD) Saquinavir/ritonavir Abacavir/ Lamivudine (if HLA*B5701 negative) Zidovudine/ lamivudine Didanosine + lamivudine Adapted from “Guidelines for the use of antiretroviral agents in HIV-1 – infected adults and adolescents,” U.S. Dept. of Health and Human Services. 2008. Rationale: recent data (KLEAN) Inclusion of boosted fosamprenavir in the “preferred” list: KLEAN: phase 3, open-label, multi-center, noninferiority study comparing the safety and efficacy of ritonavir-boosted fosamprenavir to lopinavir/ritonavir, both in combination with abacavir/lamivudine 878 treatment-naïve patients At week 48, no significant differences between arms in terms of virologic, immunologic, or metabolic response; few adverse events in similar numbers among 2 groups Eron J et al. The Lancet. August 5, 2006; 368(9534):476-482. BMS-089 96-week randomized, open-label study comparing the efficacy and safety of 400 mg atazanavir versus 300 mg of atazanavir boosted with 100 mg of ritonavir, both in combination with lamivudine and stavudine. 199 naïve patients Both arms had high rates of virologic response and were well-tolerated Malan E. et al. 13th CROI; Feb 5-8, 2006; Denver, Colorado. Abstract 107LB BMS-089 There were 10 virologic failures in the unboosted arm, compared to only 3 in the ritonavir-boosted arm; 7 people in the unboosted arm developed resistance mutations, primarily at the 184 codon, compared to only 1 in the boosted arm. Patients on ritonavir had higher rate of hyperbilirubinemia Changes in total cholesterol and triglyceride levels were significantly higher in the ritonavir-boosted arm; HDL also increased nearly identically in both arms. Gilead 934 Randomized, open-label, non-inferiority trial comparing tenofovir, emtricitabine to zidovudine, lamivudine, both in combination with Efavirenz. 517 naïve patients At week 96 significantly more patients in tenofovir / FTC arm achieved and maintained HIV RNA levels below 400 copies/mL, and had significantly greater limb fat by DEXA. The groups were similar in terms of patients achieving HIV RNA < 50 copies/mL Higher toxicity rates in zidovudine / lamivudine arm (esp. anemia), may have contributed Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. Joel E. Gallant et al., for the Study 934 Group. The New England Journal of Medicine. January 19, 2006;354(3):251-260. Acceptable but inferior options Nelfinavir Inferior virologic efficacy Pregnancy: good tolerability and adequate PK data Stavudine / lamivudine Significant toxicities: peripheral neuropathy, lipoatrophy, lactic acidosis and hepatic steatosis, pancreatitis Use if preferred or alternative dual NRTI combination cannot be used ARV components NOT recommended as initial therapy Darunavir No data DDI + Tenofovir Potential for CD4 decline, virologic failure, selection of resistance mutations Indinavir Inconvenient dosing, fluid requirement, nephrolithiasis Tipranavir No data Enfuvirtide No clinical trial experience; injections Zalcitabine + ZDV Inferior virologic efficacy, higher adverse effects ARV Regimens not recommended at any time ARV Rationale Exception Monotherapy or dual-NRTI regimens Rapid development of resistance, inferior antiviral activity Triple NRTI High rate of early failure or non-response Atazanavir+indinavir Additive hyperbilirubinemia and nephrolithiasis Amprenavir oral solution Large amount of propylene glycol Didanosine + stavudine Overlapping toxicity, eg peripheral neuropathy, pancreatitis, lactic acidosis with hepatic steatosis No other options, benefits outweigh risks Efavirenz in first trimester or in women with child-bearing potential Teratogenic in primates No other options, benefit outweighs risk Nevirapine initiation in naïve women with CD4>250 or men with CD4>400 cells/mm3 Potentially fatal hepatic events Benefits clearly outweighs risk Trizivir®, and possibly tenofovir + Combivir® May 2007 update For HIV/HBV co-infected patients, entecavir should not be used for the treatment of HBV infection without concomitant treatment for HIV. Previous in vitro data showed no significant activity against HIV-1; but recent case-series of 3 patients reported decline in HIV-RNA and emergence of M184V mutations in one co-infected patient on entecavir monotherapy. Supplement to the Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents – October 2006. Why Do Treatments Fail adherence side effects – acute and longer-term baseline resistance or cross-resistance use of less potent antiretroviral regimens sequential monotherapy drug levels and drug interactions tissue reservoir penetration other, unknown reasons M184V Arises rapidly on 3TC or FTC therapy Continued antiviral activity in presence of drug and mutation decreased viral replication fitness Presence of M184V slows the evolution of thymidine analogue mutations (TAMs) Increased susceptibility to ZDV, d4T, TDF Modest decreased susceptibility to ddI and ABC TAMs Emerge gradually with ongoing failure of ZDV or d4T Rare with ddI, TDF, ABC in absence of thymidine analogue Development of TAMs tends to follow distinct pathways of mutation at either codons 41 and 215, or at codons 67, 70, 219 McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603. K65R Selected by TDF and less frequently ABC in the absence of thymidine analogue Decreased susceptibility to TDF, ABC, and ddI Activity of TDF may be partially retained with M184V present Increases susceptibility to ZDV McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603. L74V Selected by ABC or ddI in the absence of a thymidine analogue Decreases susceptibility to ABC and ddI Does not decrease susceptibility to TDF or thymidine analogues McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603. NNRTI mutations Long term virologic response to sequential NNRTI use is poor, particularly when 2 or more mutations are present K103N, Y188L, or G190A mutations likely prevent the clinical utility of all NNRTI’s currently approved Importance of most mutations depends on the presence of Y181C, which has an impact only in the presence of at least 1 other mutation (important for Etravirine) Johnson VA et al. Topics in HIV Medicine 2007; 15(4): 119-125. NNRTI hypersusceptibility Longer duration of NRTI use, prior use of zidovudine, and abacavir or zidovudine resistance have been associated with enhanced susceptibility to NNRTIs (defined as IC50 of >2.5-fold less than that of wild-type reference strain) Greater short term reductions in viral load in patients with hypersusceptibility to efavirenz, who received that drug as salvage therapy Hirsch M. CID 2003;37:113-128. Protease gene mutations Major mutations Selected first in the presence of drug, or shown at the virologic or biochemical level to lead to an alteration in drug binding or an inhibition of viral replication Effect on drug susceptibility phenotype Minor mutations Emerge later, by themselves do not have significant effect on phenotype, but may improve replicative fitness in the presence of major mutations Presence of at least 2 key mutations (e.g., D30N, G48V, I50V, V82A/F/T/S, I84V, and L90M) generally confers broad cross-resistance to most currently available PIs “boosting” with low dose ritonavir may result in higher and more prolonged drug concentrations and greater suppression of viral variants that contain a limited number of mutations Hirsch M. CID 2003;37:113-128. Envelope gene mutations Entry of HIV-1 into cell involves attachment mediated by gp120 binding to CD4, chemokine coreceptor binding, and association of 2 trimeric helical coils (HR-1 and HR-2) located in the ectodomain of gp41 into a 6-helix bundle that brings virus and cell membranes closer together, allowing fusion T-20 (enfuvirtide) binds HR-1 and blocks association with HR-2, inhibiting fusion and viral entry Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125. Entry inhibitors Mutations at gp41 codons 36-45 are associated with an average 20-fold increase from baseline IC50 CCR5 inhibitors: Maraviroc activity is limited to patients with only R5-using virus detectable; some cases of failure during therapy are associated with outgrowth of X4 virus that preexists as a minority population below the level of detection Mutations in the gp120 molecule that allow the virus to bind R5 receptors in the presence of drug have been described Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125. Integrase mutations Raltegravir failure was associated with integrase mutations in 2 distinct genetic pathways defined by 2 or more mutations including: A major mutation at either Q148H/K/R or N155H, and 1 or more minor mutations The potential for nephrotoxicity with tenofovir is an important consideration in patients who have A) hyperpigmentation B) severe anemia C) baseline renal insufficiency D) none of the above th e ab in s al of re n on e e D )n lin as e )b C ov e u. .. ia an em e ev er )s B yp e )h A 20 rp ig m en ta t io n 0% 0% 0% 0% Tenofovir – renal issues Several case reports noting development of renal insufficiency in patients on tenofovir, some without prior history of renal dysfunction Nephrotoxicity involving tubular dysfunction with Fanconi syndrome noted in toxicological studies, dose-limiting toxicity in animal studies Tenofovir – renal issues Two similar nucleotide analogues, cidofovir and adefovir, have been associated with doselimiting, renal tubular cell toxicity in patients in infectious hepatitis or cytomegalovirus infection Renal toxicity is mediated by proximal tube epithelial cells that express human renal organic anion transporter (hOAT1) and actively uptake these drugs Figure 1. Renal biopsy image by light microscopy showing acute tubular injury with loss and irregularity of tubular epithelial cells (hematoxylin and eosin strain; original magnification, ×100). Inset, prominent nuclear enlargement with hyperchromatic and smudged chromatin (hematoxylin and eosin stain; original magnification, ×400). Tenofovir – renal issues Package insert revision 2005: dose should be adjusted for patients with creatinine clearance of <50 mL/min. Cockcroft-Gault equation: (140-age) x (lean body weight in kg) x 0.85 (females) / 72 x plasma creatinine CD4 and viral load seem not to be predictors of renal toxicity Patients on tenofovir should be monitored closely for early signs of tubulopathy (glycosuria, proteinuria, acidosis, mild creatinine increases) every 2 weeks for the first 2 months; therapy should be stopped if any signs of tubulopathy develop Karras et al. CID 2003; 36: 1070-1073; Zimmerman et al. CID 2006; 42: 28390. More important clinical trials The SMART study ACTG 5142 TITAN SMART Strategies for Management of AntiRetroviral Treatment Randomized, prospective study: 33 countries, 80% in North America and Europe Median CD4 597, 72% had viral load <400 copies/mL 5,472 HIV-infected adults with CD4 >350 Control group took ART continuously “viral suppression group” “drug conservation group” took therapy episodically (initiated when CD4 <250, stopped when >350) El-Sadr W et al. N Engl J Med 2006; 355(22):2283-2296 SMART Results: Trial halted by DSMB with a mean follow up time of only 16 months Greater risk of clinical disease progression events and overall death in drug conservation group Greater risk of serious renal, hepatic, and cardiovascular events Rather than protect patients, the withdrawal of therapy increased risk of death from any cause, including that of opportunistic infections. Cardiovascular, hepatic, and renal disease, which are often associated with ART, were greater in the treatment interruption arm. ACTG 5142 Phase 3, randomized, open-label study comparing three regimens: lopinavir/ritonavir + 2 NRTI; Efavirenz vs. 2 NRTI; lopinavir/ritonavir + efavirenz 753 ART-Naive patients with viral load >2,000 NRTIs were chosen by clinicians and patients; initially only one provided at no cost (extended-release stavudine…later tenofovir was added) Week 96 ACTG 5142 Proportion of patients with VL < 50 copies/mL statistically significantly greater in Efavirenz arm Median increase in CD4 count was significantly higher in the lopinavir arm Those patients in the NRTI-sparing arm had significantly higher fasting triglyceride levels (14% grade 3, compared to 6% in lopinavir arm, 3% in efavirenz arm); 45% moderate of severe laboratory abnormality No resistance to lopinavir was observed; however, resistance to efavirenz was detected in nearly half of patients who failed this regimen; NRTI resistance was more common with virologic failure on efavirenz as well Riddler S. et al. New England Journal of Medicine, May 15, 2008. Riddler S, et al. 96 week data from ACTG 5142 Virologic success (%) Regimen continuation <200 copies <50 copies CD4 increase Lopinavir /r + efavirenz 73 61 92 83 268 Lopinavir /r + 2 NRTI 67 54 86 77 285 Efavirenz + 2 NRTI 76 60 93 89 241 TITAN Phase 3 study comparing darunavir/r and lopinavir/r in patients with VL < 1000 copies/mL, on stable but failing regimen for at least 12 weeks 604 patients randomized to open label lopinavir/r or darunavir/r, both with optimized background selected based on resistance testing (T-20 and investigational drugs excluded) Previous lopinavir therapy exclusion criteria Data from week 48 present at IDSA 2007, San Diego TITAN Both PIs were well tolerated, only 7% discontinued due to toxicity Lipid level elevation similar between the groups; higher incidence of diarrhea in lopinavir arm (42% vs. 32%), rash in darunavir arm (16% vs. 7%) Significantly more patients in darunavir arm achieved VL <50; fewer patients in darunavir arm had virologic failure (10% vs 22%), and had primary PI mutations (21% vs. 36%) **among patients with baseline lopinavir fold-change of greater than 10-fold, only 28% achieved VL <50 (greater virologic failure driven by baseline phenotypic resistance to lopinavir??) TITAN – 48 weeks efficacy results DRV/r LPV/r P value VL<50 71 60 0.005 VL<400 77 67 <0.0001 CD4 increase 88 61 0.33 Adapted from Hardy WD et al. IDSA 2007; San Diego, CA. Abstract 1209. Newly available ARVs MERIT MOTIVATE BENCHMRK MERCK 004 Integrase cross-resistance Effects on lipid parameters DUET MERIT: Maraviroc vs Efavirenz in Treatment-Naive Patients Stratified by HIV-1 RNA < or 100,000 copies/mL and by Northern or Southern Hemisphere Antiretroviral-naive patients infected with CCR5-tropic HIV-1 and HIV-1 RNA 2000 copies/mL (N = 740) Week 48 primary endpoint Week 96 MVC 300 mg twice daily + ZDV/3TC (n = 360) EFV 600 mg once daily + ZDV/3TC (n = 361) MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at end of phase IIB (Week 16) Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CI Saag M, et al. IAS 2007. Abstract WESS104. MERIT: Patients With VL < 50 Copies/mL by baseline VL EFV patients more likely to discontinue due to AE 90 80 – Efficacy: 4.2% MVC patients more likely to discontinue due to lack of efficacy – Overall: 26.9% – AE: 4.2% Patients, % – Overall : 25.2% – AE: 13.6% EFV 100 71.6 70 69.6 MVC 66.6 59.6 60 50 40 30 20 10 0 n= 211 204 BL VL < 100,000 copies/mL 150 156 BL VL ≥ 100,000 copies/mL – Efficacy: 11.9% Saag M, et al. IAS 2007. Abstract WESS104. MOTIVATE: Maraviroc in TreatmentExperienced Patients With R5 Virus Randomized, double-blind, placebo-controlled, parallel phase IIb/III studies 44% failed screening with X4 or dual/mixed virus detected Primary endpoint: mean change in HIV-1 RNA at Week 24 Based on MOTIVATE data FDA approved MVC in August 2007 for use in treatment-experienced patients with R5-tropic virus only 2:2:1 randomization; stratified by ENF use and VL Patients infected with R5; HIV-1 RNA ≥ 5000 copies/mL; stable ART or no ART for ≥ 4 weeks; previous ART experience with ≥ 1 agent (≥ 2 for PIs) from 3 of the 4 antiretroviral drug classes for ≥ 6 months or documented resistance to members of 3 of 4 classes (MOTIVATE 1: N = 601, Canada, US; MOTIVATE 2: N = 475, Europe, Australia, US) Week 24 planned interim analysis MVC 150 mg or 300 mg* twice daily + OBR† MVC 150 mg or 300 mg* once daily + OBR† Placebo + OBR† *Patients receiving PI (other than TPV) or DLV received 150 mg; all others received 300 mg. †OBR: 3-6 ARVs. Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB. Week 48 MOTIVATE 1 and 2: Combined Virologic and Immunologic Efficacy MVC + OBR associated with significantly greater virologic suppression than placebo plus OBR in treatment-experienced patients – Increased activity observed with de novo use of enfuvirtide, LPV/RTV Outcome Placebo+ OBR MVC QD + OBR MVC BID + OBR VL<400 28 55‡ 61‡ VL<50 23 44‡ 45‡ Mean CD4 increase 57 109 106 *HIV-1 RNA value imputed as baseline if patient discontinued before 24 weeks. †Patients with missing values were classified as failures unless they were responders at Weeks 20 and 32. ‡P = .0001 vs placebo group. Gulick RM, et al. IAS 2007. Abstract WEPEB116LB. Maraviroc dosing With CYP3A inhibitors: 150 mg po BID PIs (except tipranavir) Ketoconzale, itraconazole, clarithromycin With NRTIs, nevirapine, tipranavir / ritonavir,enfuvirtide: 300 mg po BID (recommended dose) With CYP3A inducers: 600 mg (2 tabs) po BID Efavirenz Rifampin Carbamazepine Phenytoin phenobarbital Tropism testing “Trofile”: co-receptor tropism assay detects R5 vs. X4 virus Monogram biosciences HIV RNA > 1000 copies/mL required Protocol 004: Raltegravir vs Efavirenz in Treatment-Naive Patients Treatment-naive patients (n = 198) with VL > 5000 copies/mL and CD4+ > 100 cells/mm3 randomized to one of 4 doses of RAL (100, 200, 400, 600 mg BID) or EFV (600 mg QD) each with TDF + 3TC Patient Outcome, % RAL 100 mg (n = 39) RAL 200 mg (n = 40) RAL 400 mg (n = 41) RAL 600 mg (n = 40) EFV 600 mg (n = 38) VL < 400 copies/mL Week 24 95 85 98 95 95 Week 48 97 85 98 90 87 VL < 50 copies/mL Week 24 87 85 93 95 92 Viral dynamics substudy: second-phase decay may be accelerated with RAL[2] Week 48 85 83 88 88 87 Markowitz M, et al. IAS 2007. Abstract TUAB104. 2. Murray JM, et al. IAS 2007. Abstract TUAB103. Protocol 004: RAL Associated With Fewer Lipid Effects vs EFV RAL well tolerated with no dose-related toxicities Dizziness, headache, and atypical dreams more frequent with EFV Total cholesterol, LDL-cholesterol, triglycerides not increased by RAL Mean change from baseline, mg/L RAL 100-600mg EFV 600mg QD BID P value Total chol -2.3 +20.7 <0.001 LDL -7.5 +3.0 0.016 TG -1.0 +49.5 0.068 *All RAL dose groups combined. Markowitz M, et al. IAS 2007. Abstract TUAB104. BENCHMRK Double blind clinical trial: pts assigned to 200, 400 or 600 mg of MK-0518 BID along with OBT or placebo with OBT 178 patients with at least one resistance mutation in each of 3 drug classes, VL > 5,000, CD4 above 50 14% placebo group achieved VL<50 by week 24 65, 57, 67% achieved VL<50 taking 3 doses of MK-0518 Co-administration of T-20 boosted responses by about 20% in the MK-0518 arms BENCHMRK 1 and 2: Raltegravir (MK0518) in Treatment-Experienced Pts Randomized, double-blind, placebo-controlled, parallel phase III studies Primary endpoints: HIV-1 RNA, CD4+ cell counts, and adverse events at Week 16 Primary endpoints: Week 16 HIV-infected, triple-class resistant, HIV-1 RNA > 1000 copies/mL Raltegravir 400 mg twice daily + OBR* BENCHMRK-1 (n = 232) BENCHMRK-2 (n = 230) BENCHMRK-1 (N = 350) (Europe, Asia/Pacific, Peru) BENCHMRK-2 (N = 349) (North, South America) *Selected investigational antiretrovirals permitted in OBR. Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB. Planned duration: Week 48 Placebo + OBR* BENCHMRK-1 (n = 118) BENCHMRK-2 (n = 119) BENCHMRK 1 and 2: VL < 400 copies/mL (ITT, NC = F) Raltegravir + OBR Patients With HIV-1 RNA < 400 copies/mL (%) 100 Placebo + OBR 100 BENCHMRK-1 BENCHMRK-2 77% 80 77% 80 60 P < .001 at Week 16 60 P < .001 at Week 16 40 40 43% 41% 20 20 0 0 0 2 4 158 n= 230 12 16 Weeks 229 n= 118 118 81 Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB. n= 119 119 n= 232 8 12 16 Weeks 230 24 0 2 4 8 24 128 69 BENCHMRK 1 and 2: VL < 50 copies/mL (ITT, NC = F) Raltegravir + OBR Patients with HIV-1 RNA < 50 copies/mL (%) 100 100 BENCHMRK-1 80 Placebo + OBR BENCHMRK-2 80 61% 62% 60 60 P < .001 at Week 16 P < .001 at Week 16 40 40 33% 20 36% 20 0 0 0 2 4 158 n= 230 12 16 Weeks 229 n= 118 118 81 Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB. n= 119 119 n= 232 8 12 16 Weeks 230 24 0 2 4 8 24 128 69 BENCHMRK 1 and 2: VL < 400 c/mL at Wk 16 by Specific Agents in OBR Raltegravir + OBR n 447 230 Overall Efficacy Data Placebo + OBR 79 43 Efficacy by Agents in OBR Enfuvirtide Darunavir + + 44 23 + – 42 24 – + 80 47 – – 191 90 + : First use in OBR – : No use in OBR 98 87 90 63 90 55 29 0 Statistical analysis: virologic failure carried forward. Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB. 20 40 60 Patients (%) 74 80 100 Raltegravir and ?malignancies Malignancy Conclusions • In the original application, an imbalance in rates of malignancies was noted. The malignancy types and rates in the raltegravir group are those anticipated in a severely immunodeficient HIV/AIDS population and are consistent with reported rates in the literature. A history of malignancy prior to enrollment was common and many of the malignancies in the raltegravir group were likely present at time of study entry or were recurrences of prior diagnosed malignancies. • Based on an updated analysis of the same study cohorts, the imbalance in rates of malignancies has not been sustained with additional follow-up. This is consistent with the possibility that the original imbalance was a function of small numbers of cases and relatively imprecise estimates of rates. • While the updated analysis is reassuring, the total amount of safety follow-up is limited and additional data are needed. Further follow-up is proposed in the Risk Management Plan. Excerpted from Merck Briefing Document for FDA Hearing Sept 5, 2007 Raltegravir and malignancy ".....Overall, the rates and kinds of malignancies seen in patients receiving raltegravir in the clinical development program approximate the rates and kinds of malignancies reported in the literature for patients with HIV/AIDS.... ....It is also noteworthy that in the patients receiving raltegravir who ultimately developed a malignancy, the median CD4 cell count was 122 cells/mm3 and all patients with malignancy had a history of AIDS, a known independent risk factor for malignancy. Most of the malignancies encountered are associated with well known risk factors for malignancy such as AIDS, oncogenic viruses (papillomavirus infection, hepatitis B virus infection), and tobacco. Figure 19 displays Kaplan-Meier estimates of time to malignancies for the double-blind phase of Protocols 004, 005, 018, and 019. Of note, no events occurred in the raltegravir arm after month 4 in this analysis. Figure 19 Kaplan-Meier Plot of Time to Malignancy-Double-Blind Phase Phase II and III Studies Original Application Figure 20 displays Kaplan-Meier estimates of time to malignancies for the double blind phase of Protocols 004, 005, 018 and 019 cumulatively seen over 18 months of therapy in this updated malignancy analysis. Figure 20 Kaplan-Meier Plot of Time to Malignancy-Double-Blind Phase Phase II and III Studies Cumulative Update as of 09-Jul-2007 Note: These data have not been reviewed by the FDA. Integrase Inhibitor Resistance and Cross-Resistance Protocol 004: VF in 5 RAL recipients (3%) 3 had no detected integrase mutations 1 had N155H + M184M/I/V 1 had N155H + other mutations (V151I, D232D/N, G163G/R) Separate report of 2 patients with VF on elvitegravir (EVG)/RTV, with no VL response during first week after switch to RAL Suggests high level of cross-resistance between first 2 integrase inhibitors Patient 1 had N155H and 3 other integrase mutations at VF (VL: 840 copies/mL) on EVG/RTV Regained viral suppression (< 50 copies/mL) after addition of DRV/RTV to RAL Patient 2 had Q148R and 4 other integrase mutations at VF (VL: 10,700 copies/mL) on EVG/RTV Failed to regain suppression after addition of DRV/RTV to RAL Markowitz M, et al. IAS 2007. Abstract TUAB104. 2. DeJesus E , et al. IAS 2007. Abstract TUPEB032 . DUET-1 and -2: Etravirine + DRV/RTVContaining OBR Phase III Trials Week 24‡ HIV-infected patients with virologic failure on current HAART regimen, history of ≥ 1 NNRTI resistance mutations, ≥ 3 PI mutations, HIV-1 RNA > 5000 copies/mL ETR 200 mg BID* + DRV/RTV-containing OBR† Placebo + DRV/RTV-containing OBR† (DUET-1: N = 612 DUET-2: N = 591) *New formulation equivalent to 800 mg BID with old formulation. †Investigator-selected OBR to consist of DRV/RTV (600/100 mg/mL) + ≥ 2 NRTIs ± enfuvirtide. ‡Planned Week 24 analysis: primary endpoint HIV-1 RNA < 50 copies/mL (TLOVR) Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48. Katlama C, et al. IAS 2007. Abstract WESS204.2. Mills A, et al. IAS 2007. Abstract WESS204.1. Week 48 DUET-1 and -2: Virologic Response at Week 24 (TLOVR Analysis) VL < 50 copies/mL, % 100 80 DUET-1 DUET-2 P = .0003 ETR Placebo P = .005 62% 60 56% 44% 40 39% 20 0 P ETR P ETR Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48. Katlama C, et al. IAS 2007. Abstract WESS204.2. Mills A, et al. IAS 2007. Abstract WESS204.1. DUET-1 and -2: BL ETR Mutations and Virologic Response at Week 24 V90I L100I V106I Y181C/I/V A98G K101E/P V179D/F G190A/S Presence of ≥ 3 ETR mutations associated with response similar to placebo + OBR – 70% of patients had 0 or 1 ETR resistance mutations at BL Patients With HIV-1 RNA < 50 copies/mL (%) 13 mutations associated with ETR resistance 100 90 80 70 60 50 40 30 20 10 0 – 14% of patients had ≥ 3 ETR resistance mutations at BL 0 1 2 3 4 5 No. of BL ETR Mutations Patients (%) Katlama C, et al. IAS 2007. Abstract WESS204.2. 40 30 16 8 5 1 Investigational ARVs Vicriviroc – ACTG 5211 Elvitegravir CCR5 monoclonal antibody – PRO 140 others ACTG 5211: Phase II Trial of Vicriviroc in Treatment-Experienced Patients Stratified by enfuvirtide use and baseline CD4+ count < or ≥ 50 cells/mm³ Antiretroviralexperienced patients with HIV-1 RNA ≥ 5000 copies/mL and R5-only virus on ritonavircontaining regimen (N = 118) Failing regimen Gulick R, et al. J Infect Dis 2007;196:304-312. Day 14 Week 48 Placebo (n = 28) Vicriviroc 5 mg once daily (n = 30) Discontinued Vicriviroc 10 mg once daily (n = 30) Vicriviroc 15 mg once daily (n = 30) OBR (includes 100-800 mg Ritonavir) ACTG 5211: Patients with HIV-1 RNA < 50 copies/mL at 24 and 48 Weeks VCV + RTV-containing OBR associated with sustained Placebo antiviralVicriviroc activity at Week 48 10 mg Vicriviroc 15 mg 100 90 Patients, % 80 70 60 50 40 40 37 27 30 20 10 27 11 7 0 Week 24 Gulick R, et al. J Infect Dis 2007;196:304-312. Week 48 ACTG 5211: Safety, Tolerability, and Tropism on Failure Incidence of grade 3/4 AEs comparable among arms (P ≥ .6) 10 patients developed malignancies (4 additional patients since Week 24) Vicriviroc: 8 patients Non-Hodgkin’s lymphoma: n = 2 – Hodgkin’s disease: n = 2 Gastric adenocarcinoma: n = 1 – Squamous cell carcinoma: n = 1 Basal cell carcinoma: n = 1 – Kaposi sarcoma recurrence: n = 1 Placebo: 2 patients Squamous cell carcinoma: n = 2 9 (35%) of 26 patients with VF on vicriviroc had dual/mixed or X4 virus detected Gulick R, et al. J Infect Dis 2007;196:304-312. PRO 140 1302: Effects of a Single IV Humanized CCR5 Antibody Infusion PRO 140 0.5 mg/kg single IV infusion (n = 10) Patients with asymptomatic R5-tropic HIV-1 infection, HIV-1 RNA > 5000 copies/mL, CD4+ cell count > 250 cells/mm3 (with nadir > 200), and no antiretroviral therapy for ≥ 3 months PRO 140 2.0 mg/kg single IV infusion (n = 10) PRO 140 5.0 mg/kg single IV infusion (n = 10) (N = 39) Mean Change in VL, log10 copies/mL 0.5 59-day follow-up Placebo (n = 9) Placebo 0.5 mg/kg 2 mg/kg 5 mg/kg 0.0 -0.5 -1.0 ‡ -1.5 † ‡ -2.0 0 ‡ ‡ 10 † * *P ≤ .01 †P ≤ .001 ‡P ≤ .0001 ‡ ‡ 20 Saag MS, et al. IAS 2007. Abstract WESS201. 30 Study Day 40 50 60 The HLA-B*5701 genotype has been shown to be a predictive risk factor for A) poor CD4+ cell response B) ABC hypersensitivity C) insulin resistance D) lipoatrophy y tr op h )l ip oa ce re s ul in D is ta n ity iti v )i ns C hy C )A B B A )p oo r CD 4+ pe rs e ce ll 20 ns re ... 0% 0% 0% 0% New testing available HLA-B*5701 testing for Abacavir hypersensitivity (HSR) – LabCorp, Quest; PCR on whole blood or buccal swab to determine presence of HLAB5701 allele HSR observed in about 5% of patients in clinical trials; 89% of cases occur in the first 6 weeks of therapy with ABC Most have multiple symptoms (fever, rash, myalgias, arthralgias, etc…) Ziagen package insert; GSK 2003; J Antimicrob Chemother. 2007; 59:591-593. SHAPE: Retrospective Case-Control Study CASES CONTROLS Black and white subjects with clinically suspected ABC HSR (CS-HSR) Black and white subjects enrolled in KLEAN, ALOHA, CNA30027, CNA30032 ABC skin patch test and HLA-B*5701 White: n = 130 Black: n = 69 Identify ABC-tolerant subjects White: n = 202 Black: n = 206 Skin patch test positive Skin patch test negative White: n = 42 Black: n = 5 White: n = 85 Black: n = 63 Clinical Infectious Diseases. Volume 46, Issue 7, Page 1111–1118, Apr 2008 . SHAPE: Sensitivity and Specificity of HLA-B*5701 CS-HSR confirmed by HLA-B*5701 100% 100 Sensitivity of HLA-B*5701 96% Specificity of HLA-B*5701 100% 99% Sensitivity/Specificity of HLA-B*5701, % 90 80 70 60 44% 50 40 14% 30 20 10 0 57/130 42/42 194/202 10/69 5/5 204/206 CS-HSR Skin Test Positive Control CS-HSR Skin Test Positive Control White Black Clinical Infectious Diseases. Volume 46, Issue 7, Page 1111–1118, Apr 2008 Case 1 46 year old male diagnosed in 2004; initial CD4 400 cells/mm3; VL 55,000 copies/mL 2 years later CD4 decreased to 230, VL increased to 150,000, and the patient opts to begin ART: Tenofovir / emtricitabine Atazanavir 300mg + Ritonavir 100 mg After 6 months his CD4 is 450, VL <50 Case 1 The patient reports good tolerance of regimen and overall good health; he uses loratadine and pseudoephedrine for occasional bouts of seasonal rhinitis / sinusitis He also reports occasional overeating and binge drinking, accompanied by rare episodes of heartburn Case 1 A few months later after having missed a regular quarterly visit, the patient’s CD4 is 290 and VL 27,500; repeat testing confirms On questioning the patient reveals having missed occasional doses of ritonavir, in an attempt to reduce diarrhea and bloating, and having initiated over the counter omeprazole nearly daily, 20-40 mg In addition to reinforcing the importance of adherance to ritonavir, as well as the other drugs in his ARV regimen, what next steps would you take? sc o C )a dv i se to di to se dv i )a B 0% di sc o tie pa th e se dv i )a A 0% nt i.. . nt .. 0% nt i.. . A) advise the patient to avoid omeprazole within 12 hours of taking atazanavir B) advise to discontinue atazanavir and intensify the regimen, increasing the dose to 400 mg /day C) advise to discontinue omeprazole and order resistance testing 20 Genotype reveals the following mutations: RT: K65R, M184V, G190A PI: I50L, G73S Which regimen would you choose at this juncture? A) new boosted PI + NRTI B) new boosted PI + NRTI plus enfuvirtide C) NNRTI plus NRTIs 0% 0% N pl us RT I )N N C ew )n B A )n ew bo bo os te os te d d PI + PI + ... ... 20 RT I s 0% Case 1 Genotype reveals likely lack of susceptibility to approved NNRTIs (G190A); although he has not been exposed to this class he may have acquired the mutation at initial infection or subsequent reinfection Use of a fusion inhibitor is unnecessary in this case to construct a regimen with at least 2, ideally 3 active agents; reserving active agents for future use is an important strategy in HIV management Based on resistance mutations, which combination would you choose? (M184V, K65R, G190A) A) Tenofovir + emtricitabine B) Zidovudine + lamivudine C) Abacavir + lamivudine D) Stavudine + lamivudine .. m iv . la vu di ne vi r+ D )S ta ca )A ba C + la m iv u i.. . la m + di ne id ov u )Z B A )T en o fo v ir + em tri c i.. . 20 ... 0% 0% 0% 0% Case 1 Genotype pattern suggests susceptibility to abacavir, didanosine, and tenofovir would most likely be reduced The M184V may increase susceptibility to zidovudine in the presence of 3TC or FTC Stavudine likely remains phenotypically active Cased on recent clinical trial data, treatment history, and genotype, which boosted PI would you choose? 0% rit o av ir / av )D ar un C B )L op in a vi r/ m pr en os a )F A vi r na v r.. . ir / 20 0% ir 0% rit on a A) Fosamprenavir / ritonavir B) Lopinavir / ritonavir C) Darunavir / ritonavir Case 1 All 3 choices are reasonable and have a good likelihood of achieving undetectable HIV-1 RNA; the patient has minimal PI resistance (I50L confers resistance to atazanavir, G73S confers broad PI resistance, but likely would have little impact unaccompanied by another major PI mutation) Based on the results of TITAN, darunavir/ritonavir out-performed lopinavir/ritonavir at 48 weeks in less treatmentexperienced patients (31% naïve, 38% had received 1 PI) Case 1 POWER-1 demonstrated the superiority of darunavir/ritonavir over investigatorselected comparator PIs in triple-class experienced patients (in combination with OBT) KLEAN and CONTEXT demonstrated efficacy and noninferiority of boosted fosamprenavir in comparison with lopinavir/ritonavir, in both naïve and experienced patients, respectively Case 2 50 year old male initially diagnosed in 1987, RF MSM; initial CD4 800, nadir about 150. + history of Kaposi’s sarcoma, recurrent molluscum, and esophageal candidiasis ART regimens: 1992-1995: zidovudine monotherapy; CD4 241 1995-1996: zidovudine + lamivudine; CD4 327, VL 100K 1996-1998: zidovudine + lamivudine + indinavir; CD4 708 1998-2003: didanosine+ ritonavir + saquinavir; CD4 580, VL 236K 2003-2004: lamivudine + didanosine + lopinavir / ritonavir; CD4 336, VL 111 K Diagnosed with acute HBV infection, +sAg and eAg Case 2 In 2004, virtual phenotype/genotype shows: RT: M184V, 41L, 210W, 215Y PI: 54V, 71V, 82A Data for atazanavir and fosamprenavir not yet available Based on this resistance pattern and the patient’s history, what regimen would you choose at this juncture? A) Zidovudine / lamivudine + lopinavir / ritonavir B) Tenofovir / emtricitabine + nevirapine C) Tenofovir / emtricitabine + stavudine + efavirenz D) Tenofovir / emtricitabine + efavirenz + fosamprenavir + 20 ritonavir i.. . ir / em tr ic i.. . D )T en o fo v ir / em tr ic i.. . C )T en o fo v ir / fo v en o )T B A )Z id ov u di ne /l em tr ic am iv . .. 0% 0% 0% 0% Case 2 He begins new regimen of tenofovir and FTC, + boosted fosamprenavir, + efavirenz: CD4 >600; VL <400 consistently for > 1 year. The patient requests regimen simplification in 1/07 due to pill burden and fatigue, GI side effects, and lipodystrophy. He attempts to enroll in a local clinial trial examining the role of rosiglitazone in HIV-related lipodystrophy. What do you recommend now? th e ve ge gi ha n to C )c e gr e )a B 0% gi m .. th e in ... ge an ch a e )r ef us A 0% p. .. 0% re A) refuse a change in regimen, reinforce the importance of compliance B) agree to give the patient a “drug holiday” (structured treatment interruption) C) change the regimen to tenofovir / emtricitabine / efavirenz, which has just 20 become available Case 2 The patient begins tenofovir / emtricitabine / efavirenz. 3 months later he feels great, is tolerating the drug extremely well, and his CD4 count is still 708 (35%)… BUT…his viral load has climbed to 6437…now what? A) continue his current regimen…the viral load was probably a “blip” and will come back down. B) restart fosamprenavir and ritonavir. C) repeat the viral load and order resistance testing with plans to completely change his regimen. Case 2 Genotype/virtual phenotype performed in April 2007 reveals the same NRTI mutations as previously (M184V and multiple TAMs); he now has the K103N, and the same PI mutations as he had in 2003, with phenotypic sensitivity only to saquinavir, tipranavir, and darunavir. What happened? A) although he reported 100% compliance, he probably missed doses and developed resistance to the NNRTIs B) the lack of three fully active drugs put more selection pressure on efavirenz, bringing out an archived virus with the K103N mutation, which he acquired either at initial infection or later by reinfection C) the geno/pheno from 2003 used a different technique and was therefore probably wrong Case 2 The patient is concerned about his viral rebound, and is willing to begin a new regimen. Based on most recent geno/pheno the patient begins tenofovir/emtricitabine, stavudine, darunavir, and ritonavir. His regimen now contains 3 drugs active against HIV and 2 active against hepatitis B. Although he is tolerating the regimen well, and his viral load became undetectable after 6 weeks (CD4 still about 700), he is now concerned about increasing abdominal girth and wasting of the extremities, which has been a chronic problem, but he’s noticed it even more since initiating the new regimen. What might be a reasonable option for this patient in the near future, assuming his viral load remains undetectable? ra v ir. . m ra lte g ar av to rti de ub s )s C B )s ub s tit u tit u te te uv i en f dd )a 0% .. 0% h. . 0% A A) add enfuvirtide to his current regimen B) substitute maraviroc for darunavir / ritonavir C) substitute raltegravir for stavudine, with the possibility of adding / substituting etravirine at a later date 20