1 Emerging Therapies for Emerging Therapies for HIV Multiple Drug HIV Multiple Drug Resistance Resistance Nelson Nelson Vergel Vergel www.salvagetherapies.org www.salvagetherapies.org This information (and any accompanying printed This information (and any accompanying printed material) is not intended to replace the attention or material) is not intended to replace the attention or advice of a physician or other health care professional. advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first or treat a specific disease or condition should first consult with and seek clearance from a qualified health consult with and seek clearance from a qualified health care professional. care professional. The AIDS pandemic The AIDS pandemic Adults and children infected with Adults and children infected with HIV/AIDS, end 2002 HIV/AIDS, end 2002 North America 980,000 North America 980,000 Caribbean 440,000 Caribbean 440,000 Latin America 1,500,000 Latin America 1,500,000 North Africa & Middle East 550,000 North Africa & Middle East 550,000 Sub-Saharan Africa 29,400,000 Sub-Saharan Africa 29,400,000 East Asia & Pacific 1,200,000 East Asia & Pacific 1,200,000 S & SE Asia 6,000,000 S & SE Asia 6,000,000 Australia & New Zealand 15,000 Australia & New Zealand 15,000 Western Europe 570,000 Western Europe 570,000 Eastern Europe & Central Asia 1,200,000 Eastern Europe & Central Asia 1,200,000 3.4% 3.4% 4.8% 4.8% 5.6% 5.6% 11.1% 11.1% 13.2% 13.2% 13.5% 13.5% 15.8% 15.8% 17.8% 17.8% 20.8% 20.8% 29.0% 29.0% 2001-02 increase Source: UNAIDS Availability of HIV Medications in the World Source: WHO, http://www.who.int/3by5/en/ Coverage Menos del 10% No hay informes de personas en tratamiento HIV Medications Have HIV Medications Have Decreased The Death Rate Decreased The Death Rate NNRTI ’ 87 87 ’ 91 91 ’ 92 92 ’ 94 94 ’ 95 95 ’ 96 96 ’ 97 97 ’ 98 98 ’ 99 99 ’ 00 00 ’ 88 88 ’ 89 89 ’ 90 90 NRTI NRTI PI PI Approved Antiretrovirals Approved Antiretrovirals Retrovir Retrovir Norvir Norvir Invirase Invirase Crixivan Crixivan Fortovase Fortovase Kaletra Kaletra Viracept Viracept Ziagen Ziagen Combivir Combivir Videx Videx Hivid Hivid Zerit Zerit Epivir Epivir Trizivir Trizivir Rescriptor Sustiva Viramune ’ 01 01 Viread Viread Emtriva Emtriva Reyataz Reyataz ’ 02 02 ’ 03 03 ’ 93 93 Agenerase Agenerase FI FI FUZEON FUZEON Retrovir, Epivir, Combivir, Ziagen, Retrovir, Epivir, Combivir, Ziagen, Agenerase Agenerase, , Lexiva Lexiva and Trizivir are trademarks of GlaxoSmithKline. Videx, Zerit, and Trizivir are trademarks of GlaxoSmithKline. Videx, Zerit, Sustiva and Reyataz are Sustiva and Reyataz are trademarks of Bristol trademarks of Bristol-Myers Squibb. Norvir and Kaletra are registered trademarks of Ab Myers Squibb. Norvir and Kaletra are registered trademarks of Abbott. Crixivan is registered trademark of Merck. bott. Crixivan is registered trademark of Merck. Viramune is registered trademark of Boehringer Ingelheim. Virace Viramune is registered trademark of Boehringer Ingelheim. Viracept and Rescriptor are registered trademarks of Agouron. Viread a pt and Rescriptor are registered trademarks of Agouron. Viread and nd Emtriva are trademarks of Gilead. Emtriva are trademarks of Gilead. Hivid Hivid, Invirase, Fortovase and FUZEON are registered trademarks of Ro , Invirase, Fortovase and FUZEON are registered trademarks of Roche Laboratories. che Laboratories. Lexiva Lexiva Aptivus Aptivus 05 05
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Emerging Therapies for Emerging Therapies for HIV Multiple Drug HIV Multiple Drug
ResistanceResistanceNelson Nelson VergelVergel
www.salvagetherapies.orgwww.salvagetherapies.org
This information (and any accompanying printed This information (and any accompanying printed material) is not intended to replace the attention or material) is not intended to replace the attention or
advice of a physician or other health care professional. advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, Anyone who wishes to embark on any dietary, drug,
exercise, or other lifestyle change intended to prevent exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first or treat a specific disease or condition should first
consult with and seek clearance from a qualified health consult with and seek clearance from a qualified health care professional.care professional.
The AIDS pandemicThe AIDS pandemicAdults and children infected with Adults and children infected with
HIV/AIDS, end 2002HIV/AIDS, end 2002
North America980,000
North America980,000
Caribbean440,000Caribbean440,000
Latin America1,500,000
Latin America1,500,000
North Africa& Middle East
550,000
North Africa& Middle East
550,000
Sub-Saharan Africa29,400,000
Sub-Saharan Africa29,400,000
East Asia & Pacific
1,200,000
East Asia & Pacific
1,200,000
S & SE Asia6,000,000
S & SE Asia6,000,000
Australia& New Zealand
15,000
Australia& New Zealand
15,000
Western Europe
570,000
Western Europe
570,000
Eastern Europe& Central Asia1,200,000
Eastern Europe& Central Asia1,200,000
3.4%3.4%
4.8%4.8% 5.6%5.6%
11.1%11.1%
13.2%13.2%
13.5%13.5%
15.8%15.8% 17.8%17.8%
20.8%20.8%
29.0%29.0%
2001-02 increase
Source: UNAIDS
Availability of HIV Medications in the World
Source: WHO,
http://www.who.int/3by5/en/
Coverage
Menos del 10%No hay informes de personas en tratamiento
HIV Medications Have HIV Medications Have Decreased The Death RateDecreased The Death Rate
Retrovir, Epivir, Combivir, Ziagen, Retrovir, Epivir, Combivir, Ziagen, AgeneraseAgenerase, , LexivaLexiva and Trizivir are trademarks of GlaxoSmithKline. Videx, Zerit, and Trizivir are trademarks of GlaxoSmithKline. Videx, Zerit, Sustiva and Reyataz are Sustiva and Reyataz are trademarks of Bristoltrademarks of Bristol--Myers Squibb. Norvir and Kaletra are registered trademarks of AbMyers Squibb. Norvir and Kaletra are registered trademarks of Abbott. Crixivan is registered trademark of Merck. bott. Crixivan is registered trademark of Merck. Viramune is registered trademark of Boehringer Ingelheim. ViraceViramune is registered trademark of Boehringer Ingelheim. Viracept and Rescriptor are registered trademarks of Agouron. Viread apt and Rescriptor are registered trademarks of Agouron. Viread and nd Emtriva are trademarks of Gilead. Emtriva are trademarks of Gilead. HividHivid, Invirase, Fortovase and FUZEON are registered trademarks of Ro, Invirase, Fortovase and FUZEON are registered trademarks of Roche Laboratories.che Laboratories.
Phase IPhase IUniversity of PittsburghUniversity of PittsburghAutologousAutologous dendriticdendritic cell HIV vaccination w/conserved cell HIV vaccination w/conserved HIVHIV--derived peptidesderived peptides
At least 3 active drugs leftAt least 3 active drugs left
From 2From 2--3 active drugs left3 active drugs left
Less than 2 drugs leftLess than 2 drugs left
Main Objective of Salvage Therapy:Main Objective of Salvage Therapy:
If possible, patients with multiple drug resistanceIf possible, patients with multiple drug resistanceshould should not not be exposed to be exposed to
monotherapy of any kind, or to "virtual monotherapy", monotherapy of any kind, or to "virtual monotherapy", where one new drug is added to a failing regimen for where one new drug is added to a failing regimen for
any appreciable length of timeany appreciable length of time.
Maintain mutationsDecrease fitness
Delay progression
Accumulate newmutations
Develop resistance to drugs in
development
Continued Therapy in Patients With Virologic Failure: A Delicate Balance
Add New Active DrugAdd New Active DrugKeep Current RegimenKeep Current Regimen(Holding Pattern)(Holding Pattern)
In combination therapy, only the active drugs countA new drug is not necessarily an active drugAdding a new class is associated with better outcomesWhen to use a new drug, and when to waitWaiting: Choosing a “holding regimen”The role of replication capacity
Considerations for Salvage Therapy
4
Fusion Inhibition: Optimal Use of Fuzeon (T-20)
Kaletra (TORO), Aptivus (RESIST) and TMC 114 (POWER) with or without Fuzeon- VirologicResponse (Viral load reduction of 1 log or more)
24%
55%
20
40
60
80
100
<400 copies/ml
Patie
nts
(%)
TORO
LPV/rFUZEON + LPV/r
20
40
60
80
100
37%
67%
<50 copies/ml
Patie
nts
(%)
POWER
TMC114/rFUZEON + TMC114/r
≥1 log10 dropfrom baseline
37%
70%
20
40
60
80
100
Patie
nts
(%)
RESIST
TPV/rFUZEON + TPV/r
New Fuzeon Approaches
• New data show that after failing Fuzeon and stopping the drug for 16 weeks, some sensitivity returns
• After Fuzeon failure and interruption for 4 months, some clinicians are starting to use a pulsing mode with Fuzeon that lasts 4 weeks
• The reintroduction of Fuzeon (in those who have used it in the past) when starting one or more new active drugs needs to be investigated
Predictors of Best Therapeutic Response to Fuzeon (96 week data)Factors associated with ↑ likelihood of achieving HIV-1 viral load < 400 copies/mL in both arms
Patients receiving Fuzeon consistently had better virologic and immunologic outcomesThose with higher CD4 cells, lower viral loads and who started one or more active agents did better on the drug
< .00011.6-3.32.3≥ 2 active ARVs in OB< .00011.6-3.42.4Prior experience with ≤ 10 ARVs.00321.2-2.61.8Baseline HIV-1 RNA < 100,000 copies/mL
Needle-Free Injection System for Administration of Enfuvirtide
Montaner J, et al. IAS 2005. Abstract WeFo0205.
Use of needle-free gas-powered injection system
– Compared with standard needles and syringes
No significant differences in Fuzeon plasma levels
ISR(injection site reactions)-related signs and symptoms significantly reduced
24 pts evaluated reported that needle-free injector was similar or easier to use than needles
Needle Biojectiongas-powered
device
Biojector B2000
Not FDA approved yet with the Not FDA approved yet with the use of use of FuzeonFuzeon. In studies now. In studies now
Preliminary data show lower Preliminary data show lower incidence of injection site incidence of injection site reactionsreactions
To be approved by the FDA soon. To be approved by the FDA soon. Available at Available at BioScriptBioScriptPharmacies ( former Pharmacies ( former StatscriptStatscript))
Choosing and Using Antiretrovirals for Multiclass-Experienced Patients
On the Horizon: New ClassesIntegrase Inhibitors– MK-0518 (phase III)
▪ Phase II studies fully enrolled; BID dosing▪ Phase III enrolling in March▪ Potent agent that may reduce viral load significantly, specially when
used with TMC 114 (protease)
– GS-9137▪ Phase II studies in development
Maturation Inhibitors– PA-457
▪ Proof-of-principle study demonstrated short-term activity. Phase II to start late in 2006
CCR5 and CXCR4 Are Co-receptors for HIV Binding and Entry
TT--cell surfacecell surfaceCCR5
CD4
CXCR4
39
Prevalence of HIV Co-receptor Usage
17<183NaiveHomer cohortb
15085NaiveC & W cohortc
6094NaiveMaraviroc (UK-427,857) Phase 2a
12088NaiveGSKd
Experienced
Experienced
Population
48250ViroLogicf
34462TORO 1/2e
R5/X4X4R5Study/Source
a Data on file d Demarest et al. ICAAC 2004. Abstract H-1136b Harrigan PR et al. 15th IAC 2004. Abstract MoPeB3117 e Whitcomb et al. CROI 2003. Abstract 557c Moyle GJ et al. 15th IAC 2004. Abstract WePeB5725 f Huang et al. ICAAC 2002. Abstract 2040 clinicaloptions.com/hiv
Choosing and Using Antiretrovirals for Multiclass-Experienced Patients
Increasing Prevalence of X4- or R5/X4-Tropic Virus At Lower CD4+ CountsCCR5:
Pts with early-stage HIV disease tend to have pure R5-tropic virus
CXCR4:With advanced disease, X4- or dual-tropic virus emerges
Associated with more rapid clinical and immunologic progression
CCR5 inhibition could select for more virulent X4-tropic virus
Moyle G, et al. ICAAC 2004. Abstract 1135.
16 16 14.8
41.9 40
01020304050607080
> 300
248
Prev
alen
ce o
f X4
or R
5/X4
(%)
90100
201-300
104
101-200
81
51-100
31
< 50
50
CD4+ Cell Countn =
HIV-1
HIV-1 envelope
glycoprotein
TT--cell surfacecell surface
gp120
gp41
CCR5
CD4
gp120
gp41HIV-1
TT--cell surfacecell surface
CCR5
CD4
8
HIV Attachment andFusion Targets for InhibitionHIV Attachment andHIV Attachment andFusion Targets for InhibitionFusion Targets for Inhibition
Phase II studies in naives (+Phase II studies in naives (+CombivirCombivir) and treatment experienced (+ OBT) ) and treatment experienced (+ OBT) stopped due to liver toxicitystopped due to liver toxicity
VicrivirocVicriviroc (SCH(SCH--417690)417690) –– ScheringSchering--PloughPloughPhase II study in naives (boosted Phase II study in naives (boosted qd+Combivirqd+Combivir vsvs Sustiva+CombivirSustiva+Combivir) )
stopped due to increased viral load in some patients. Treatment stopped due to increased viral load in some patients. Treatment experienced study (+OBT) completely enrolled by ACTG. We are waiexperienced study (+OBT) completely enrolled by ACTG. We are waiting ting for data.for data.
Concerns about potential increase in cancers.Concerns about potential increase in cancers.
MaravirocMaraviroc (UK(UK--427857)427857)-- PfizerPfizerBoth naBoth naïïve and treatment experienced studies ongoing. One case ve and treatment experienced studies ongoing. One case
of liver toxicity (1/1000 patients) in naof liver toxicity (1/1000 patients) in naïïve study that may have ve study that may have not been caused by the study drug. Lower dose arm stopped in not been caused by the study drug. Lower dose arm stopped in treatment natreatment naïïve study due to lack of efficacy. A separate study ve study due to lack of efficacy. A separate study looking at drug efficacy in dual tropics patients (R5/X4) is looking at drug efficacy in dual tropics patients (R5/X4) is completed.completed.
clinicaloptions.com/hiv
Choosing and Using Antiretrovirals for Multiclass-Experienced Patients
How Will We Use CCR5 Inhibitors?Initial therapy– PROs:
– Naive patients less likely to have X4- or R5/X4-tropic virus
– Maturation inhibitor + other entry inhibitor(s) + ?
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ResourcesResources11--800800--TRIALSTRIALS--A for studies in your areaA for studies in your areaClinicalTrials.govClinicalTrials.gov. Type key words . Type key words ““ HIV treatment HIV treatment experiencedexperienced”” in search box for all studiesin search box for all studiesSalvageTherapies.orgSalvageTherapies.org-- My web siteMy web siteNATAP.orgNATAP.org-- Complete conference reports and daily Complete conference reports and daily updatesupdatesACRIA.orgACRIA.org-- Another good directory of clinical trials Another good directory of clinical trials ClinicalOptions.comClinicalOptions.com-- for professionalsfor professionalsTAGTAG’’ss pipeline report pipeline report ((http://www.aidsinfonyc.org/tag/tx/antiretroviralsPipelineJuly05.http://www.aidsinfonyc.org/tag/tx/antiretroviralsPipelineJuly05.html)html)
Join Join ATACATAC’’ss Drug Development Committee (Drug Development Committee (www.atacwww.atac--usa.org)usa.org)-- Be an activist and be in controlBe an activist and be in controlJoin the largest discussion group in the internet by Join the largest discussion group in the internet by sending a blank email to sending a blank email to