New Hope for Treatment Experienced HIV (+) Patients. Treatment Experienced. Drug Resistance: Estimated Prevalence. Patients in the US- Estimate

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1 New Hope for Treatment Experienced HIV (+) Patients Nelson Vergel HIV/AIDS Pandemic 23: Adults and Children Living With HIV/AIDS 47% of Cases are Women 15.6% Eastern Europe Western 5.9% Europe & Central Asia 1,8, 4.5% North America 68, 2.8% 1,2, 9.2% East 13.6% North Africa Asia & & Caribbean Middle East Pacific 1,3, 73, 59, 13.4% 12.1% S 9.5% Sub-Saharan Saharan & SE Asia 8,2, Latin America Africa 1,9, 28,2, Australia 5.6% & New Zealand 18, 4% of Cases are Children Most via Mother to Child Transmission Trends in AIDS-Related Deaths and HAART Availability in the United States 19 Drugs How to Pick the Best Regimen? AIDS-Related Deaths Number Saquinavir Indinavir Ritonavir Nelfinavir Amprenavir Lopinavir/r ZDV ddi ddc d4t 3TC NVP DLV EFV TDF ABC CDC: Surveillance Report. 23. % Drug Resistance Drug Resistance: Estimated Prevalence HCSUS: Results representative of the 132,442 (63%) of 29, patients under care in early 1996 who survived until 1999 with HIV RNA > 5 copies/ml Total Study Population 5% Any Drug 78% Any Drug 7% NRTI 42% PI 31% Drug Resistance Detected 51% 14% NNRTI 2-3-class 3-class Treatment Experienced Patients in the US- Estimate 1 million people with HIV in the US Approx. 4, under treatment 3 Drug Class Resistance (GS=): 14 % or 56, people 2 Drug Class Resistance(GS=2): 51 % or 24, people 3 % may be co-infected with Hep C, and another 1 % with Hep B Long term survivors (monotherapy nuke era) vs new salvage patients Up to 14% of new infections may have multi-drug resistant (MDR) virus 1

2 Investigational drugs: Existing classes Investigational drugs: New classes Class Nucleoside/ nucleotide analogs Protease inhibitors NNRTIs Fusion inhibitors Drug SPD 754 (DOTC) Amdoxovir (DAPD) DPC 817 (D-D4FC; Reverset ) Alovudine (MIV 31) Racivir (+/-FTC) SN1212 GW385 P-1946 TMC 114 Tipranavir GW678248X (prodrug = GW695634G) CSIC DAPY/DATA UC781 TMC 125 Capravirine NB-2, NB-64 T-649 T-1249 Phase I/II On hold I/II I/II I/II? II III (expanded access) IIa II III On hold 7 Class Entry inhibitors Integrase inhibitors Attachment inhibitors Coreceptor antagonists Maturation inhibitors Others CXCR4 CCR5 Drug TNX-355 (anti-cd4 Ab) BMS AL4-YV T-22 TAK-779 KRH HCL AMD-7 PRO 14 TAK-22 RANTES analogs AK62 SCH-D GW87314 UK-427,857 V-165 Styrylquinolones L-87,81 S-136 PA-457 D-amino acid peptides TAT-TAR antagonist RNAse H inhibitors Zinc finger inhibitors Phase II II I II II II II/III I Phase I 8 Drug Resistance Treatment Failure Fuzeon: Mechanism of Action Viral Fitness Now What? Mutations Video 19 Approved Drugs Tests to Measure Resistance to Medications GENESEQ HIV TEST REPORT 2

3 PHENOSENSE HIV TEST REPORT Replication Capacity RC value indicates the ability of the patient s s virus to replicate relative to the median RC of a wild-type population of viruses Median RC value of a wild-type population of viruses defined as 1% RC is given at the bottom of a PhenoSense (phenotype) test Fitness / Replicating Capacity (RC) Testing New test compares RC of patient virus with RC of wild-type Increasing amount of clinical data showing low RC associated with slower disease progression Another piece of information to help make a treatment decision Can I delay treatment or should I start? Should I stop treatment or should I switch medications? RC available with phenotypic tests from ViroLogic Protease Combinations for Multi-Drug Resistance Do You Have Enough Medication in your Blood? Norvir Boosted Protease Inhibitors Kaletra Invirase+Norvir Agenerase+Norvir Lexiva+Norvir Crixivan+Norvir Reyataz+ Norvir 3

4 Be Aware of Interactions Between PIs Commonly Used Doses for Double Boosted PI combinations Double PI Studies in Treatment Experienced Patients How Do Treatment Experienced Patients Access Drugs in the US? Treatment IND Pros: : Very early access for those who need it. Physician chooses best combo. Cons: : Difficult paper work- local IRBs involved. Patients may be exposed to unknown toxicities. Death vs Risks Phase II- Safety/Dose Inclusion/exclusion barriers (genotype, allowed OBT,liver, etc)- Optimum dose/safety not established Phase III - Efficacy Inclusion/exclusion (genotype, allowed OBT, liver,etc) barriers Open Label Safety Study (pre- approval) Just like Phase III- protocol requirements plus CD4 limits Expanded Access (pre- approval) No CD4/genotype limits but possible liver exclusions. Physician chooses best OBT freely. Barriers in Entering Salvage Drug Protocols Do you have the right mutations? T cells over 5? Is your virus CCR5 tropic? Do you have Hep B or C coinfection?? Do you have high liver enzymes? Have you taken T-2? T Drugs for Treatment Experience Patients Phase II (now enrolling): Pfizer CCR5 Entry Inhibitor UK-427,857 Schering CCR5 Entry Inhibitor Tanox TNX 355 CD4 attachment inhibitor GW87314 (CCR5 Antagonist ) Tibotec s TMC 114 Protease Tibotec s TMC 125 NNRTI Phase III (finished): Boeringher Ingelheim s Protease Tipranavir (closed to enrollment). Currently available through Open Label Safety Study for those under 1 T cells. Expanded Access soon Pfizer Capravirine (NNRTI) - Closed 4

5 Main Objective of Salvage Therapy: Treatment Strategies for Optimizing the Benefits of New Agents If possible, patients with multiple drug resistance should not be exposed to monotherapy of any kind, or to "virtual monotherapy", where one new drug is added to a failing regimen for any appreciable length of time. How to Switch: Use at least 3 fully effective drugs Continued Therapy in Patients With Virologic Failure: A Delicate Balance Maintain mutations Decrease fitness Delay progression Accumulate new mutations Develop resistance to drugs in development Katzenstein/Albrecht AIDS 23 Considerations for Salvage Therapy In combination therapy, only the active drugs count In combination therapy, only the active drugs count Early HAART in NRTI-experienced patients often amounted to serial monotherapy New drugs (eg, PIs) added to a failing NRTI-based regimen How many active drugs are required? 2 vs 3? Active PI + active NNRTI: probably OK 3TC + active NNRTI: maybe not 5

6 Considerations for Salvage Therapy Considerations for Salvage Therapy In combination therapy, only the active drugs count A new drug is not necessarily an active drug In combination therapy, only the active drugs count A new drug is not necessarily an active drug Adding a new class is associated with better outcomes Adding a New Class Is Associated With Better Outcomes Patients With HIV-1 RNA < 4 Copies/mL (%) % 13% T-2 + OB (n = 661) OB (n = 334) 26% Patients With CD4+ Cell Count Increase 1 Cells/mm 3 (%) Study Week Study Week ITT: D/C or SW = F % 1% 31% Considerations for Salvage Therapy In combination therapy, only the active drugs count A new drug is not necessarily an active drug Adding a new class is associated with better outcomes When to use a new drug, and when to wait Arasteh K, et al. IAC 24. Abstract MoOrB158. When To Use a New Drug, and When to Wait Is there at least 1 new class available, and if so, will it be well protected? What is the expected prognosis with continued nonsuppressive therapy? What are the resistance consequences of continued nonsuppressive therapy? How can I maintain the right mutations without allowing the wrong ones to emerge? When will new drugs be available, and will they be active against the patient s s virus? Considerations for Salvage Therapy In combination therapy, only the active drugs count A new drug is not necessarily an active drug Adding a new class is associated with better outcomes When to use a new drug, and when to wait Waiting: Choosing a holding regimen 6

7 Partial Treatment Interruption Change in HIV-1 RNA (log 1 copies/ml) PI interruption (n = 18) NRTI interruption (n = 7) Week Change in HIV-1 RNA (log 1 copies/ml) Week Potential Rationale for Partial Treatment Interruption Toxicity Preserve future options Avoid accumulation of mutations that may decrease activity of future agents In some cases, this may mean stopping the most active agents Safety of this approach depends on disease stage, rate of CD4 decline, and estimates for availability of new drugs Deeks SG, et al. CROI 23. Abstract 64. Guidelines for Choosing a Holding Regimen Never use an NNRTI NNRTI mutations have no beneficial impact on fitness Accumulation of additional mutations may result in cross-resistance to 2nd generation NNRTIs Use 3TC or FTC Simple, well tolerated drugs M184V decreases fitness Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations Considerations for Salvage Therapy In combination therapy, only the active drugs count A new drug is not necessarily an active drug Adding a new class is associated with better outcomes When to use a new drug, and when to wait Waiting: Choosing a holding regimen The role of replication capacity CD4-VL Disconnect: Can Impaired Replicating Capacity Be Used Strategically? Change in CD4+ Cell Count (cells/mm 3 ) 2 1 Deeks, et al. J Infect Dis 2;181:946. Incomplete viral control Complete viral control Weeks Change in HIV-1 RNA (log 1 copies/ml) Considerations for Salvage Therapy In combination therapy, only the active drugs count A new drug is not necessarily an active drug Adding a new class is associated with better outcomes When to use a new drug, and when to wait Waiting: Choosing a holding regimen The role of replication capacity Using the new drug: Too soon, too late, or just right? 7

8 Using the New (and Active) Agent: Too Soon, Too Late, or Just Right? Too soon: New drug used in combination with 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 new agents, or use deferred until other new agents available NEW DRUGS IN EXISTING CLASSES: NUCLEOSIDE: REVERSET PIs: TIPRANAVIR AND TMC 114 NON-NUCLEOSIDE: NUCLEOSIDE: TMC 125 XV International AIDS Conference Activity of New Nucleoside D-d4FC D (Reverset( Reverset) ) in Treatment-Experienced Patients Previous data in naive pts: nearly 1.8 log VL reduction at day 1 New data on 8 experienced pts; mean -.8 log VL reduction at day 1 Log 1 Change in HIV-1 RNA Naive pts mg QD 1 mg QD Murphy et al. Abstract MoOrB mg QD Placebo -2. Dosing Period Days Log 1 Change in HIV-1 RNA Experienced pts 2 mg QD Dosing Period Days Reverset Studies For more information about Reverset s protocols,e mail clinical.trials@incyte.com 46 RESIST-1 Study Design Investigational Protease Inhibitor: Role of Tipranavir Randomized, open-label study Baseline resistance testing Optimized regimen designed Enfuvirtide use designated Week 48 Triple classexperienced patients with multi-pi resistance (N = 62) TPV/r (5/2 mg BID) + OB regimen (n = 311) APV/r, IDV/r, LPV/r, or SQV/r* + OB regimen (n = 39) * Comparator PI (CPI) selected by physician based on treatment history and baseline resistance testing 48-week extension phase 8

9 RESIST-1: Baseline Susceptibility and Agents Prescribed Comparator PI regimens (CPI) LPV, 61% IDV, 4% SQV, 21% APV, 14% 36% of patients also received Fuzeon Baseline median HIV-1 RNA, 4.8 log 1 copies/ml Baseline CD4+ cell count, 123 cells/mm 3 Hicks C, et al. ICAAC 24. Abstract 1137a. Median fold change in IC 5 Baseline Phenotypic Susceptibility (VIRCO) TPV LPV IDV SQV APV n = RESIST-1: Tipranavir (TPV) vs Other PIs (CPI) - Virologic Response Patients with HIV-1 RNA < 4 copies/ml (%) 1 TPV/r (n = 311) 9 CPI/r (n = 39) 8 ITT: Noncompleter = Failure 7 P < % % Week Hicks C, et al. ICAAC 24. Abstract 1137a. Patients with HIV-1 RNA < 5 copies/ml (%) TPV/r (n = 311) CPI/r (n = 39) ITT: Noncompleter = Failure P < % 1% Week CPI: Compatator protease inhibitor RESIST-1: Virologic Impact of Use of Fuzeon (Enfuvirtide-ENF) RESIST-1: Summary of Results Patients (%) HIV-1 RNA 1 < 4 copies/ml 9 at Week TPV/r CPI/r TPV/r CPI/r All Fuzeon 25 HIV-1 RNA < 5 copies/ml at Week TPV/r CPI/r TPV/r CPI/r All Fuzeon Week 24 Outcome Treatment response, % Change in CD4+ cell count, cells/mm 3 Grade 3/4 ALT, % Grade 3/4 triglycerides, % Grade 3/4 cholesterol, % TPV/r <.1 TPV/r shows superior efficacy vs other boosted PIs Use of enfuvirtide with tipranavir/ritonavir substantially improves virologic outcome Safety profile of TPV/r consistent with other PIs, except incidence of elevated ALT, AST, triglycerides, and cholesterol CPI/r P Value <.1 <.1 <.1 <.1 Hicks C, et al. ICAAC 24. Abstract 1137a. Hicks C, et al. ICAAC 24. Abstract 1137a. BI : Virologic Response Median Change in HIV-1 RNA From Baseline (log 1 copies/ml) PI/r + OB TPV added to boosted-pi + OB TPV/r TPV/APV/r TPV/LPV/r TPV/SQV/r Weeks of Treatment < 2% used Fuzeon Interactions Between TPV/r and Concomitant PIs Addition of tipranavir lowered trough plasma concentrations of other PIs Change From Week 2 to Week 4 (%) SQV APV LPV 84% 51% AUC C max C min 45% Walmsley S, et al. IAC 24. Abstract WeOrB1236. Walmsley S, et al. IAC 24. Abstract WeOrB

10 BI : Incidence of GI Events During Single-boosted PI Therapy First 14 days Pts With an Adverse Event (AE), n (%) Any AE Diarrhea NOS Nausea Vomiting NOS TPV/r (n = 66) 37 (56.1) 9 (13.6) 3 (4.5) (.) APV/r (n = 76) 46 (6.5) 12 (15.8) 1 (13.2) 5 (5.3) SQV/r (n = 75) 46 (61.3) 4 (5.3) 8 (1.7) 3 (4.) LPV/r (n = 79) 44 (55.7) 8 (1.1) 6 (7.6) 1 (1.3) Total (N = 296) 173 (58.4) 33 (11.1) 27 (9.1) 8 (2.7) Tipranavir- Lessons Learned It reduces blood levels of other protease inhibitors in the blood, even in the presence of 2 mg of Norvir It can reduce HIV viral load by 1.2 logs even in patients with multi-drug resistance. The effect only lasts for 4 weeks if no active drug is present in the background. Fuzeon improves effectiveness of Tipranavir GI and liver side effects do not seem greater than other protease inhibitors Tipranavir should never be started without at least one new active drug with it Walmsley S, et al. IAC 24. Abstract WeOrB1236. Tipranavir expanded Access Program to start soon. Talk to your physician about it. You should not start Tipranavir without another active drug (non protease inhibitor) in your genotype. Roche Labs is starting a Fuzeon access program for those starting Tipranavir. New PI: TMC-114 in PI-experienced patients Open, randomized study in 5 patients failing therapy: CD4 >5 cells/mm 3 ; HIV RNA >2 c/ml Prior use of PIs for >2 2 months each Current PIs: LPV/r 54%, IDV 14%, NFV 6% Boosted PIs 86% Resistance: 46% resistant to all PIs 27% sensitive to 1 PI Median fold-change to TMC-114 = 1.7 PI substitution with 1 of 3 doses of TMC RTV vs no substitution AEs: Diarrhea 3% Rash 5% Headache 15% Arasteh K, et al. 1 th CROI, Boston 23, #8; Koh Y, et al. ibid, #549 TMC 125- A new NNRTI It might work following resistance to Sustiva (EFV) or Viramune (NVP). In a clinical trial conducted in England, 16 HIV-positive who were failing either Sustiva (efavirenz)) or Viramune (nevirapine)) were switched to TMC-125 (in combination with the nucleoside analogues they were taking previously). Twelve of these 16 patients had mutations in their virus known to cause high-level resistance to both Sustiva and Viramune. Eight days after switching to TMC-125, viral load decreased, on average, by.86 log and seven patients saw their viral load decrease by more than 1 log. TMC 125 (NNRTI) Inclusion Criteria HIV-1 1 infection, male or female Viral load at screening > 1, copies/ml Documented genotypic evidence of resistance to currently available NNRTIs, either present at screening, or from prior genotypic analysis At least 3 primary PI resistance mutations on screening VirtualPhenotype Previous NRTI experience for at least 3 months Exclusion Criteria: Chronic HBV and/or HCV with AST and/or ALT > 3 x ULN 1

11 HIV Attachment and Fusion Targets for Inhibition BMS TNX-355 CD4 Binding CD4 gp41 gp12 V3 loop Coreceptor Binding Coreceptor Antagonists UK-427,857 GW SCH D AMD-7 Virus-Cell Fusion Fuzeon Fusion Inhibition: Optimal Use of Fuzeon (T-2) Cell Membrane CCR5/CXCR4 (R5/X4) Moore JP, et al. PNAS. 23;1: Background on Fuzeon (T-2) First and only inhibitor of HIV-1 entry to be approved for clinical use Member of subclass of fusion inhibitors Active in treatment-experienced patients Synthetic peptide consisting of 36 amino acids Administered twice daily by subcutaneous self-injection Baseline Demographics Durability of Virologic Response Median HIV-1 RNA, log 1 copies/ml Median CD4+ cell count, cells/mm 3 Median number of prior ARVs Median years since initiating ARVs Prior AIDS-defining events, % Median prior NRTI duration, yrs Median prior NNRTI duration, yrs Median prior PI duration, yrs ENF + OB (n = 661) OB alone (n = 334) Patients With HIV-1 RNA < 4 Copies/mL (%) 1 T-2 + OB (n = 661) 9 ITT: DC or SW = F OB (n = 334) % 26% % Study week Delfraissy J-F, et al. CROI 23. Abstract 568. Arastéh K, et al. IAC 24. Abstract MoOrB

12 Durability of Immunologic Response Response to Fuzeon + OB Change From Baseline (On-Treatment) Patients With CD4+ Increase 1 Cells/mm 3 (%) 1 T-2 + OB (n = 661) 9 ITT: DC or SW = F OB (n = 334) % 4 31% 3 2 1% Study week Mean in CD4+ Cell Count (cells/mm 3 ) Mean in HIV-1RNA (log 1 copies/ml) Study Week 166 CD4+ cell count Viral load -2.7 Arastéh K, et al. IAC 24. Abstract MoOrB158. Virologic Response in Patients With Active Kaletra and 2 Other Active ARVs Added benefit with Fuzeon even among pts with active Kaletra and 2 other active drugs Predictors of Best Therapeutic Response to Fuzeon Factors associated with likelihood of achieving HIV-1 viral load < 4 copies/ml in both arms Patients With HIV-1 RNA < 4 log 1 copies/ml (%) ENF+OB n = 98 OB alone n = 59 Study Week ITT, D/C + Switch = Failure P <.5 52% 27% Variable Baseline CD4+ cell count > 1 cells/mm 3 Baseline HIV-1 RNA < 1, copies/ml Prior experience with 1 ARVs 2 active ARVs in OB Odds Ratio <.1.32 <.1 <.1 Patients receiving Fuzeon consistently had better virologic and immunologic outcomes % CI P Value Miralles D, DeMasi R. IDSA 24. Abstract 921. Injection Site Reactions With Fuzeon Patients With ISRs (%) Mild tenderness Moderate pain Severe pain: Analgesics required or limiting usual activities Weeks Arastéh K, et al. IAC 24. Abstract MoOrB

13 Fuzeon: Once Daily (2 injections) vs Twice a Day Benefits of FUZEON ASAP For patients who are starting treatment with FUZEON in combination with an investigational drug in expanded access, FUZEON ASAP will provide: Up to a 6-day supply of FUZEON This includes an immediate shipment of a 3-day supply at no cost to the patient or clinician. One additional 3-day supply can be made available if reimbursement is still pending. Reimbursement Assistance Services To help facilitate continued access to FUZEON, a reimbursement counselor will verify patient prescription benefits, evaluate reimbursement options, and assist with the completion of prior authorizations, where necessary. Additionally, an application to the indigent Patient Assistance Program* will be provided, if needed. Support Programs Upon request, support programs for patients will be provided, including home nurse visits to supplement initial injection training provided to the patients by the physician. Adherence Programs Upon request, adherence programs will be provided to help facilitate successful continuation of therapy and assistance throughout the duration of treatment with FUZEON. To Enroll or Obtain More Information: Call the FUZEON Answer Center FUZEON ( ) HIV Attachment and Fusion Targets for Inhibition CD4 Binding BMS TNX-355 CD4 gp41 gp12 V3 loop Cell Membrane Moore JP, et al. PNAS. 23;1: Anti-CD4 monoclonal antibody, TNX-355 Inclusion Criteria Cumulative HAART experience of a minimum of 6 months, with triple-class experience (NRTI, NNRTI, PI) Viral susceptibility to OBT during screening, determined by PhenoSense GT or similar assay Stable viral load >5, within 8 weeks prior to randomization while on stable HAART regimen for minimum 4 weeks prior to screening. CD4+ count >5 cells/ml Exclusion Criteria Prior use of Fuzeon (T 2), LIVER ENZYMES > 2.5 UPPER LIMIT Kuritzkes DR, et al. 1 th CROI, Boston 23, #13 TNX-355 by Tanox Pharmaceutical Acts by inhibiting viral fusion after virus- CD4 binding After a single infusion of TNX-355: Gradual dose-related HIV RNA reduction ( 1.9( log 1 c/ml at day 21 at highest dose) Immediate CD4 increase (approximately 1 cells/mm 3 ) No SAEs reported Further, multiple dosing studies planned, with infusions every days Kuritzkes DR, et al. 1 th CROI, Boston 23, #13 13

14 TNX-355: Phase 1b Study TNX-355 added to an unchanged ART or none for >2 2 months in 22 patients HIV RNA: 4.78 log 1 copies/ml CD4: 332 cells/µl Dose groups (IV) 1 mg/kg each week 1 mg/kg loading dose, then 6 mg/kg every 2 weeks 25 mg/kg every 2 weeks Patients (%) Reduction in Viral Load After 9 Weeks 1 95% Serious adverse events Recurrence of known >.5 >.75 >1. >1.2 >1.4 depression Change From Baseline (log 1 copies/ml) New-onset seizure Jacobson JM, et al. 11 th CROI. San Francisco, 24. Abstract % 64% 45% 23% BMS-48843: Proof-of-Concept of-concept Study 3 treatment-na naïve patients HIV RNA: 4.66 log 1 copies/ml CD4: 43 cells/µl Monotherapy for 8-days, 8 then 7-day 7 follow-up Placebo BMS mg q12 hours 18 mg q12 hours Change in viral load >1. log reduction BMS-48843: 58% of patients Placebo: % Dose-response relationship Generally well-tolerated Log 1 Copies/mL Change in HIV RNA Last Day of Dosing Placebo BMS mg BMS mg Time (days) Hanna G, et al. 11 th CROI. San Francisco, 24. Abstract 141. HIV Attachment and Fusion Targets for Inhibition Coreceptor Binding Coreceptor Antagonists UK-427,857 GW SCH AMD-7 CCR5/CXCR4 Moore JP, et al. PNAS. 23;1: * Major viral species * Essential for transmission * Present throughout disease * 5% incidence in late AIDS * Associated with more rapid progression of disease Inhibition of Coreceptor-Mediated Entry Promising interventional target CCR5 in humans 32 CCR5 mutant associated with essentially normal immune function Key coreceptor for HIV, alternative is CXCR4 Co-receptor Tropism Prevalence of R5, X4, dual-tropic Study/Source UK-427,857 Phase Population Naive R5 94% X4 % R5X4 6% Delta 32 CCR5 wt CCR5 II a Homer cohort a Naive 84% % 16% <1.5% <2% Ca. 8% TORO 1/2 b Experienced 62% 4% 34% (Essentially) No HIV Infection Delayed Progression Normal Progression ViroLogic Database c Experienced 5% 2% 48% Lui R, et al. Cell. 1996;86: Samson M, et al. Nature. 1996;382: Dean M, et al. Science. 1996;273: Huang Y, et al. Nat Med. 1996;2: Michael NL, et al. Nat Med. 1997;3: Eugen-Olsen J, et al. AIDS. 1997;11: a Data on file b Whitcomb et al, CROI 23 c Huang et al, ICAAC 22 14

15 Viral Load Decline in R5 Tropic Patients Receiving UK-427,857 Change From Baseline In Log 1 HIV RNA (copies/ml) 1 Last Day Of Dosing Placebo bid qd -1 UK-427,857 5 mg bid 1 mg bid 1 mg qd 3 mg bid 3 mg qd Days Fätkenheuer G, et al. 15 th IAC. Bangkok, 24. Abstract TuPeB CCR5 Co-Receptor Antagonist: Phase 1 Study With SCH Randomized, blinded, sequential dose-escalation escalation N=48 Dose-related decrease in HIV RNA No treatment limiting adverse events reported No QTc prolongation was reported Log 1 Copies/mL Change in HIV RNA Last Day of Dosing Placebo SCH-D mg bid 25 mg bid 5 mg bid Time (days) Schurmann D, et al. 11 th CROI. San Francisco, 24. Abstract 14LB. Reversible X4 and R5 Selection After Coreceptor Antagonist Use Research Studies in the US Go to and type in the drug s s name in the search box 1 R5 Usage (%) 5 R5 Treatment With an R5 Antagonist Treatment With an X4 Antagonist X4 1 X4 Usage (%) 5 Tipranavir/ ipranavir/ritonavir in HIV Patients with Limited Treatment Options Nationwide - This study is currently recruiting patients TNX-355 with Optimized Background Therapy (OBT) in Treatment-Experienced Subjects with HIV-1 Nationwide - This study is currently recruiting patients Safety and Effectiveness of the Oral HIV Entry Inhibitor SCH in HIV Infected Patients Nationwide - This study is currently recruiting patients Safety and Activity of the Oral HIV Entry Inhibitor AMD117 in HIV Infected Patients Alabama - This study is not yet open for patient recruitment Phase 2 study of TMC114 and low dose ritonavir in HIV-1 1 infected subjects Nationwide - This study is currently recruiting patients Moore JP, et al. PNAS. 23;1: Safety and Efficacy of PRO 542 in the Treatment of HIV-Infected Infected Patients New York - This study is currently recruiting patients Summary There is a lot of hope! One new protease to be available soon and a at least 6 new drugs in years Never start a new drug without at least another active one in your genotype test Fuzeon is an effective drug and it works better for those with more m active drugs, and those who start it earlier Tipranavir (protease) will be available soon Periodically check all research studies in clinicaltrials.gov and type your city s s and/or drug s s name Work with your doctor to find the best boosted PI or double PI background regimen for you Sometimes staying on a regimen that our virus has developed resistance to is better than no treatment at all (virus is more crippled ) Be careful with treatment interruptions if your T cells are close e to 2. Keep in mind that keeping nucleosides in your treatment at all times may be advisable, even if you have to take a medication break b due to toxicities Stay on top of information! Internet Resources For more information on clinical studies, visit type treatment experienced in search box Subscribe to a free Internet support group by sending an to: SalvageTherapies-subscribe@yahoogroups.com subscribe@yahoogroups.com Nelson Vergel s powertx@aol.com. Visit the web site Save Your Life- Become a Treatment Activist. Visit atac-usa.org 15