Antiretroviral UpdateAntiretroviral UpdateSpring 2008Spring 2008

Lisa M. Chirch, M.D.Lisa M. Chirch, M.D.

Stony Brook University - CPHEStony Brook University - CPHENY/NJ AIDS Education and Training NY/NJ AIDS Education and Training

CenterCenter

ObjectivesObjectives Review DHHS guidelines and most Review DHHS guidelines and most

recent changes / additionsrecent changes / additions Overview of recent significant clinical Overview of recent significant clinical

trial results trial results Review currently approved, available Review currently approved, available

antiretroviral (ARV) medications and antiretroviral (ARV) medications and known toxicities, idiosyncrasiesknown toxicities, idiosyncrasies

Report on new agents in the pipeline, Report on new agents in the pipeline, or under ongoing investigation in or under ongoing investigation in Phase II and III trialsPhase II and III trials

Case vignettes and discussionCase vignettes and discussion

Indications for initiating ARV therapy for the Indications for initiating ARV therapy for the chronically HIV-1 infected patientchronically HIV-1 infected patient

Clinical CategoryClinical Category CD4+ cell countCD4+ cell count RecommendationRecommendation

AIDS-defining illness AIDS-defining illness or severe symptoms*or severe symptoms*

Any valueAny value TreatTreat

AsymptomaticAsymptomatic CD4 <200/mmCD4 <200/mm33 TreatTreat

AsymptomaticAsymptomatic CD4 >200, <350CD4 >200, <350 TreatTreat

AsymptomaticAsymptomatic CD4 >350CD4 >350 Discuss risks and Discuss risks and benefits, consider benefits, consider patient comorbidities patient comorbidities and scenariosand 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 Predicted 6 month risk of AIDS according to age, CD4, and viral loadaccording to age, CD4, and viral load

Based on Poisson regression model: Based on Poisson regression model: Phillips A, et al. Phillips A, et al. AIDSAIDS 2004 (CASCADE 2004 (CASCADE Collaboration- Collaboration- CConcerted oncerted AAction on ction on SSeroeroCConversion to onversion to AAIDS and IDS and DDeath in eath in EEurope: urope: www.ctu.mrc.ac.uk/cascadewww.ctu.mrc.ac.uk/cascade

Examples: Examples: 35 year old with CD4 100, has 6 month risk of 35 year old with CD4 100, has 6 month risk of

progression to AIDS of progression to AIDS of 4.74.7% if viral load is % if viral load is 3,000; 3,000; 9.39.3% if VL is 30,000; % if VL is 30,000; 1818% if 300,000.% if 300,000.

55 year old with CD4 of 150 has 55 year old with CD4 of 150 has 4.74.7% risk if VL % risk if VL 3,000; 3,000; 18.218.2% if VL 300,000.% if VL 300,000.

55 year old with CD4 of 350 has 55 year old with CD4 of 350 has 1.21.2% risk if VL % risk if VL 3,000, 3,000, 3.63.6% if VL 100,000, % if VL 100,000, 55% if VL 300,000.% if VL 300,000.

Which of the following fixed dose Which of the following fixed dose combinations (FDCs) are designated as combinations (FDCs) are designated as

preferred initial NRTI options according to preferred initial NRTI options according to the most recent DHHS guidelines?the most recent DHHS guidelines?

A) T

DF/FTC a

nd Z

DV...

B) A

BC/3TC a

nd TD...

C) Z

DV/ABC/3

TC an...

D) A

BC/3TC a

nd ZD...

0% 0%0%0%

A) TDF/FTC and A) TDF/FTC and ZDV/3TCZDV/3TC

B) ABC/3TC and B) ABC/3TC and TDF/FTCTDF/FTC

C) ZDV/ABC/3TC and C) ZDV/ABC/3TC and TDF/FTCTDF/FTC

D) ABC/3TC and D) ABC/3TC and ZDV/3TCZDV/3TC 20

Which of the following ARVs is Which of the following ARVs is contraindicatedcontraindicated in women with CD4 in women with CD4

cell counts above 250?cell counts above 250?

A) E

favi

renz

B) N

elfin

avir

C) N

evira

pine

D) D

idan

osine

0% 0%0%0%

A) EfavirenzA) Efavirenz

B) NelfinavirB) Nelfinavir

C) NevirapineC) Nevirapine

D) DidanosineD) Didanosine

20

Which of the following regimens is Which of the following regimens is not not recommended in women who are or recommended in women who are or

may become pregnant?may become pregnant?

A) E

FV/TDF/

FTC

B) F

PV/r plu

s ABC/3

TC

C) L

PV/RTV p

lus

ZD...

D) A

ll of

the

above

0% 0%0%0%

A) EFV/TDF/FTCA) EFV/TDF/FTC

B) FPV/r plus B) FPV/r plus ABC/3TCABC/3TC

C) LPV/RTV plus C) LPV/RTV plus ZDV/3TCZDV/3TC

D) All of the aboveD) All of the above20

Preferred and Alternative ARVs in updated Preferred and Alternative ARVs in updated DHHS GuidelinesDHHS Guidelines

NNRTINNRTI PIPI 2 NRTI2 NRTI

PreferredPreferred EfavirenzEfavirenz AtazanavirAtazanavir

+Ritonavir; +Ritonavir; Fosamprenavir Fosamprenavir + ritonavir + ritonavir (BID), lopinavir/(BID), lopinavir/

ritonavir (BID)ritonavir (BID)

Tenofovir/Tenofovir/

EmtricitabineEmtricitabine

Abacavir/Abacavir/

Lamivudine (Lamivudine (if HLA*B5701 negative))

AlternativAlternativee

NevirapineNevirapine AtazanavirAtazanavir

FosamprenavirFosamprenavir

Fosamprenavir Fosamprenavir (QD)(QD)

Lopinavir/Lopinavir/

ritonavir (QD)ritonavir (QD)

Saquinavir/Saquinavir/ritonavirritonavir

Zidovudine/Zidovudine/

lamivudinelamivudine

Didanosine + Didanosine + lamivudinelamivudine

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 (Rationale: recent data (KLEANKLEAN))

Inclusion of boosted fosamprenavir in the Inclusion of boosted fosamprenavir in the “preferred” list: “preferred” list:

KLEANKLEAN: phase 3, open-label, multi-center, non-: phase 3, open-label, multi-center, non-inferiority study comparing the safety and inferiority study comparing the safety and efficacy of ritonavir-boosted fosamprenavir to efficacy of ritonavir-boosted fosamprenavir to lopinavir/ritonavir, both in combination with lopinavir/ritonavir, both in combination with abacavir/lamivudine abacavir/lamivudine

878 treatment-naïve patients878 treatment-naïve patients At week 48, no significant differences between At week 48, no significant differences between

arms in terms of virologic, immunologic, or arms in terms of virologic, immunologic, or metabolic response; few adverse events in similar metabolic response; few adverse events in similar numbers among 2 groupsnumbers among 2 groups

Eron J et al. The Lancet. August 5, 2006; 368(9534):476-482.

BMS-089BMS-089 96-week randomized, open-label 96-week randomized, open-label

study comparing the efficacy and study comparing the efficacy and safety of 400 mg atazanavir versus safety of 400 mg atazanavir versus 300 mg of atazanavir boosted with 300 mg of atazanavir boosted with 100 mg of ritonavir, both in 100 mg of ritonavir, both in combination with lamivudine and combination with lamivudine and stavudine.stavudine.

199 naïve patients199 naïve patients Both arms had high rates of virologic Both arms had high rates of virologic

response and were well-toleratedresponse and were well-toleratedMalan E. et al. 13th CROI; Feb 5-8, 2006; Denver, Colorado. Abstract 107LB

BMS-089BMS-089

There were 10 virologic failures in the unboosted There were 10 virologic failures in the unboosted arm, compared to only 3 in the ritonavir-boosted arm, compared to only 3 in the ritonavir-boosted arm; 7 people in the unboosted arm developed arm; 7 people in the unboosted arm developed resistance mutations, primarily at the 184 codon, resistance mutations, primarily at the 184 codon, compared to only 1 in the boosted arm.compared to only 1 in the boosted arm.

Patients on ritonavir had higher rate of Patients on ritonavir had higher rate of hyperbilirubinemiahyperbilirubinemia

Changes in total cholesterol and triglyceride Changes in total cholesterol and triglyceride levels were significantly higher in the ritonavir-levels were significantly higher in the ritonavir-boosted arm; HDL also increased nearly boosted arm; HDL also increased nearly identically in both arms.identically in both arms.

Gilead 934Gilead 934 Randomized, open-label, non-inferiority trial Randomized, open-label, non-inferiority trial

comparing tenofovir, emtricitabinecomparing tenofovir, emtricitabine to zidovudine, to zidovudine, lamivudine, both in combination with Efavirenz.lamivudine, both in combination with Efavirenz.

517 naïve patients517 naïve patients At week 96 significantly more patients in At week 96 significantly more patients in

tenofovir / FTC arm achieved and maintained HIV tenofovir / FTC arm achieved and maintained HIV RNA levels below 400 copies/mL, and had RNA levels below 400 copies/mL, and had significantly greater limb fat by DEXA.significantly greater limb fat by DEXA.

The groups were similar in terms of patients The groups were similar in terms of patients achieving HIV RNA < 50 copies/mLachieving HIV RNA < 50 copies/mL

Higher toxicity rates in zidovudine / lamivudine Higher toxicity rates in zidovudine / lamivudine arm (esp. anemia), may have contributedarm (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 Acceptable but inferior optionsoptions

NelfinavirNelfinavir Inferior virologic efficacyInferior virologic efficacy Pregnancy: good tolerability and Pregnancy: good tolerability and

adequate PK dataadequate PK data Stavudine / lamivudineStavudine / lamivudine

Significant toxicities: peripheral Significant toxicities: peripheral neuropathy, lipoatrophy, lactic neuropathy, lipoatrophy, lactic acidosis and hepatic steatosis, acidosis and hepatic steatosis, pancreatitispancreatitis

Use if preferred or alternative dual Use if preferred or alternative dual NRTI combination cannot be usedNRTI combination cannot be used

ARV components NOT recommended as ARV components NOT recommended as initial therapyinitial therapy

DarunavirDarunavir No dataNo data

DDI + TenofovirDDI + Tenofovir Potential for CD4 decline, Potential for CD4 decline, virologic failure, selection of virologic failure, selection of resistance mutationsresistance mutations

IndinavirIndinavir Inconvenient dosing, fluid Inconvenient dosing, fluid requirement, nephrolithiasisrequirement, nephrolithiasis

TipranavirTipranavir No dataNo data

EnfuvirtideEnfuvirtide No clinical trial experience; No clinical trial experience; injectionsinjections

Zalcitabine + ZDVZalcitabine + ZDV Inferior virologic efficacy, Inferior virologic efficacy, higher adverse effectshigher adverse effects

ARV Regimens not recommended at ARV Regimens not recommended at anyany timetime

ARVARV RationaleRationale ExceptionExceptionMonotherapy or dual-NRTI Monotherapy or dual-NRTI regimensregimens

Rapid development of Rapid development of resistance, inferior resistance, inferior antiviral activityantiviral activity

Triple NRTITriple NRTI High rate of early failure High rate of early failure or non-responseor non-response

TrizivirTrizivir®®, and possibly , and possibly tenofovir + Combivirtenofovir + Combivir®®

Atazanavir+indinavirAtazanavir+indinavir Additive Additive hyperbilirubinemia and hyperbilirubinemia and nephrolithiasisnephrolithiasis

Amprenavir oral solutionAmprenavir oral solution Large amount of Large amount of propylene glycolpropylene glycol

Didanosine + stavudineDidanosine + stavudine Overlapping toxicity, eg Overlapping toxicity, eg peripheral neuropathy, peripheral neuropathy, pancreatitis, lactic pancreatitis, lactic acidosis with hepatic acidosis with hepatic steatosissteatosis

No other options, benefits No other options, benefits outweigh risksoutweigh risks

Efavirenz in first trimester Efavirenz in first trimester or in women with child-or in women with child-bearing potentialbearing potential

Teratogenic in primatesTeratogenic in primates No other options, benefit No other options, benefit outweighs riskoutweighs risk

Nevirapine initiation in Nevirapine initiation in naïve women with naïve women with CD4>250 or men with CD4>250 or men with CD4>400 cells/mmCD4>400 cells/mm33

Potentially fatal hepatic Potentially fatal hepatic eventsevents

Benefits clearly outweighs Benefits clearly outweighs riskrisk

May 2007 updateMay 2007 update

For HIV/HBV co-infected patients, For HIV/HBV co-infected patients, entecavir should entecavir should notnot be used for the be used for the treatment of HBV infection without treatment of HBV infection without concomitantconcomitant treatment for HIV. treatment for HIV.

Previous in vitro data showed no Previous in vitro data showed no significant activity against HIV-1; but significant activity against HIV-1; but recent case-series of 3 patients recent case-series of 3 patients reported decline in HIV-RNA and reported decline in HIV-RNA and emergence of M184V mutations in emergence of M184V mutations in one co-infected patient on entecavir one co-infected patient on entecavir monotherapy.monotherapy.Supplement to the Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents – October 2006.

Why Do Treatments FailWhy Do Treatments Fail

adherenceadherence side effects – acute and longer-termside effects – acute and longer-term baseline resistance or cross-resistancebaseline resistance or cross-resistance use of less potent antiretroviral use of less potent antiretroviral

regimensregimens sequential monotherapysequential monotherapy drug levels and drug interactionsdrug levels and drug interactions tissue reservoir penetrationtissue reservoir penetration other, unknown reasonsother, unknown reasons

M184VM184V

Arises rapidly on 3TC or FTC therapyArises rapidly on 3TC or FTC therapy Continued antiviral activity in presence of Continued antiviral activity in presence of

drug and mutationdrug and mutation decreased viral replication fitnessdecreased viral replication fitness Presence of M184V slows the evolution of Presence of M184V slows the evolution of

thymidine analogue mutations (TAMs)thymidine analogue mutations (TAMs) Increased susceptibility to ZDV, d4T, TDFIncreased susceptibility to ZDV, d4T, TDF Modest decreased susceptibility to ddI and Modest decreased susceptibility to ddI and

ABCABC

TAMsTAMs

Emerge gradually with ongoing Emerge gradually with ongoing failure of ZDV or d4Tfailure of ZDV or d4T

Rare with ddI, TDF, ABC in absence Rare with ddI, TDF, ABC in absence of thymidine analogueof thymidine analogue

Development of TAMs tends to follow Development of TAMs tends to follow distinct pathways of mutation at distinct pathways of mutation at either codons 41 and 215, or at either codons 41 and 215, or at codons 67, 70, 219codons 67, 70, 219McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.

K65RK65R

Selected by TDF and less frequently Selected by TDF and less frequently ABC in the absence of thymidine ABC in the absence of thymidine analogueanalogue

Decreased susceptibility to TDF, ABC, Decreased susceptibility to TDF, ABC, and ddIand ddI

Activity of TDF may be partially Activity of TDF may be partially retained with M184V presentretained with M184V present

Increases susceptibility to ZDVIncreases susceptibility to ZDVMcComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.

L74VL74V

Selected by ABC or ddI in the Selected by ABC or ddI in the absence of a thymidine analogueabsence of a thymidine analogue

Decreases susceptibility to ABC and Decreases susceptibility to ABC and ddIddI

Does not decrease susceptibility to Does not decrease susceptibility to TDF or thymidine analoguesTDF 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 mutationsNNRTI mutations Long term virologic response to Long term virologic response to

sequential NNRTI use is poor, sequential NNRTI use is poor, particularly when 2 or more mutations particularly when 2 or more mutations are presentare present

K103N, Y188L, or G190A mutations K103N, Y188L, or G190A mutations likely prevent the clinical utility of all likely prevent the clinical utility of all NNRTI’s NNRTI’s currently currently approvedapproved

Importance of most mutations depends Importance of most mutations depends on the presence of Y181C, which has an on the presence of Y181C, which has an impact only in the presence of at least 1 impact only in the presence of at least 1 other mutation (important for other mutation (important for EtravirineEtravirine))

Johnson VA et al. Topics in HIV Medicine 2007; 15(4): 119-125.

NNRTI hypersusceptibilityNNRTI hypersusceptibility Longer duration of NRTI use, prior use Longer duration of NRTI use, prior use

of zidovudine, and abacavir or of zidovudine, and abacavir or zidovudine resistance have been zidovudine resistance have been associated with enhanced associated with enhanced susceptibility to NNRTIs (defined as ICsusceptibility to NNRTIs (defined as IC5050 of >2.5-fold less than that of wild-type of >2.5-fold less than that of wild-type reference strain)reference strain)

Greater short term reductions in viral Greater short term reductions in viral load in patients with load in patients with hypersusceptibility to efavirenz, who hypersusceptibility to efavirenz, who received that drug as salvage therapyreceived that drug as salvage therapy

Hirsch M. CID 2003;37:113-128.

Protease gene mutationsProtease gene mutations Major mutationsMajor mutations

Selected first in the presence of drug, or shown at Selected first in the presence of drug, or shown at the virologic or biochemical level to lead to an the virologic or biochemical level to lead to an alteration in drug binding or an inhibition of viral alteration in drug binding or an inhibition of viral replicationreplication

Effect on drug susceptibility phenotypeEffect on drug susceptibility phenotype Minor mutationsMinor mutations

Emerge later, by themselves do not have significant Emerge later, by themselves do not have significant effect on phenotype, but may improve replicative effect on phenotype, but may improve replicative fitness in the presence of major mutationsfitness in the presence of major mutations

Presence of at least 2 key mutations (e.g., D30N, Presence of at least 2 key mutations (e.g., D30N, G48V, I50V, V82A/F/T/S, I84V, and L90M) generally G48V, I50V, V82A/F/T/S, I84V, and L90M) generally confers broad cross-resistance to most currently confers broad cross-resistance to most currently available PIsavailable PIs

““boosting” with low dose ritonavir may result in higher boosting” with low dose ritonavir may result in higher and more prolonged drug concentrations and greater and more prolonged drug concentrations and greater suppression of viral variants that contain a limited suppression of viral variants that contain a limited number of mutationsnumber of mutations

Hirsch M. CID 2003;37:113-128.

Envelope gene mutationsEnvelope gene mutations

Entry of HIV-1 into cell involves Entry of HIV-1 into cell involves attachment mediated by gp120 binding attachment mediated by gp120 binding to CD4, chemokine coreceptor binding, to CD4, chemokine coreceptor binding, and association of 2 trimeric helical coils and association of 2 trimeric helical coils (HR-1 and HR-2) located in the (HR-1 and HR-2) located in the ectodomain of gp41 into a 6-helix bundle ectodomain of gp41 into a 6-helix bundle that brings virus and cell membranes that brings virus and cell membranes closer together, allowing fusioncloser together, allowing fusion

T-20 (enfuvirtide) binds HR-1 and blocks T-20 (enfuvirtide) binds HR-1 and blocks association with HR-2, inhibiting fusion association with HR-2, inhibiting fusion and viral entryand viral entry

Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125.

Entry inhibitorsEntry inhibitors Mutations at gp41 codons 36-45 are associated Mutations at gp41 codons 36-45 are associated

with an average 20-fold increase from baseline with an average 20-fold increase from baseline ICIC5050

CCR5 inhibitors: Maraviroc activity is limited to CCR5 inhibitors: Maraviroc activity is limited to patients with only R5-using virus detectable; some patients with only R5-using virus detectable; some cases of failure during therapy are associated with cases of failure during therapy are associated with outgrowth of X4 virus that pre-exists as a minority outgrowth of X4 virus that pre-exists as a minority population below the level of detectionpopulation below the level of detection

Mutations in the gp120 molecule that allow the Mutations in the gp120 molecule that allow the virus to bind R5 receptors in the presence of drug virus to bind R5 receptors in the presence of drug have been describedhave been described

Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125.

Integrase mutationsIntegrase mutations

Raltegravir failure was associated Raltegravir failure was associated with integrase mutations in 2 distinct with integrase mutations in 2 distinct genetic pathways defined by 2 or genetic pathways defined by 2 or more mutations including:more mutations including: A major mutation at either Q148H/K/R or A major mutation at either Q148H/K/R or

N155H, andN155H, and 1 or more minor mutations1 or more minor mutations

The potential for nephrotoxicity with The potential for nephrotoxicity with tenofovir is an important consideration tenofovir is an important consideration

in patients who havein patients who have

A) h

yper

pigm

enta

tion

B) s

ever

e an

emia

C) b

asel

ine

renal

insu

...

D) n

one

of the

above

0% 0%0%0%

A) hyperpigmentationA) hyperpigmentation

B) severe anemiaB) severe anemia

C) baseline renal C) baseline renal insufficiencyinsufficiency

D) none of the aboveD) none of the above

20

Tenofovir – renal issuesTenofovir – renal issues

Several case reports noting Several case reports noting development of renal insufficiency in development of renal insufficiency in patients on tenofovir, some without patients on tenofovir, some without prior history of renal dysfunctionprior history of renal dysfunction

Nephrotoxicity involving tubular Nephrotoxicity involving tubular dysfunction with Fanconi syndrome dysfunction with Fanconi syndrome noted in toxicological studies, dose-noted in toxicological studies, dose-limiting toxicity in animal studieslimiting toxicity in animal studies

Tenofovir – renal issuesTenofovir – renal issues

Two similar nucleotide analogues, Two similar nucleotide analogues, cidofovir and adefovir, have been cidofovir and adefovir, have been associated with dose-limiting, renal associated with dose-limiting, renal tubular cell toxicity in patients in infectious tubular cell toxicity in patients in infectious hepatitis or cytomegalovirus infectionhepatitis or cytomegalovirus infection

Renal toxicity is mediated by proximal Renal toxicity is mediated by proximal tube epithelial cells that express human tube epithelial cells that express human renal organic anion transporter (hOAT1) renal organic anion transporter (hOAT1) and actively uptake these drugsand 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 issuesTenofovir – renal issues Package insert revision 2005: dose should Package insert revision 2005: dose should

be adjusted for patients with creatinine be adjusted for patients with creatinine clearance of <50 mL/min.clearance of <50 mL/min. Cockcroft-Gault equation:Cockcroft-Gault equation:

(140-age) x (lean body weight in kg) x 0.85 (140-age) x (lean body weight in kg) x 0.85 (females) / 72 x plasma creatinine(females) / 72 x plasma creatinine

CD4 and viral load seem not to be CD4 and viral load seem not to be predictors of renal toxicitypredictors of renal toxicity

Patients on tenofovir should be monitored Patients on tenofovir should be monitored closely for early signs of tubulopathy closely for early signs of tubulopathy (glycosuria, proteinuria, acidosis, mild (glycosuria, proteinuria, acidosis, mild creatinine increases) creatinine increases) every 2 weeks for the every 2 weeks for the first 2 monthsfirst 2 months; therapy should be stopped ; therapy should be stopped if any signs of tubulopathy developif any signs of tubulopathy develop

Karras et al. CID 2003; 36: 1070-1073; Zimmerman et al. CID 2006; 42: 283-90.

More important clinical trialsMore important clinical trials

The SMART studyThe SMART study ACTG 5142ACTG 5142 TITANTITAN

SMARTSMART SStrategies for trategies for MManagement of anagement of

AAntintiRRetroviral etroviral TTreatmentreatment Randomized, prospective study: 33 Randomized, prospective study: 33

countries, 80% in North America and countries, 80% in North America and EuropeEurope Median CD4 597, 72% had viral load <400 Median CD4 597, 72% had viral load <400

copies/mLcopies/mL 5,472 HIV-infected adults with CD4 >3505,472 HIV-infected adults with CD4 >350 Control group took ART continuously “viral Control group took ART continuously “viral

suppression group”suppression group” ““drug conservation group” took therapy drug conservation group” took therapy

episodically (initiated when CD4 <250, stopped episodically (initiated when CD4 <250, stopped when >350)when >350)

El-Sadr W et al. N Engl J Med 2006; 355(22):2283-2296

SMARTSMART Results:Results:

Trial halted by DSMB with a mean follow up Trial halted by DSMB with a mean follow up time of only 16 monthstime of only 16 months

Greater risk of clinical disease progression Greater risk of clinical disease progression events and overall death in drug conservation events and overall death in drug conservation groupgroup

Greater risk of serious renal, hepatic, and Greater risk of serious renal, hepatic, and cardiovascular eventscardiovascular events

Rather than protect patients, the withdrawal of Rather than protect patients, the withdrawal of therapy increased risk of death from any cause, therapy increased risk of death from any cause, including that of opportunistic infections. including that of opportunistic infections. Cardiovascular, hepatic, and renal disease, Cardiovascular, hepatic, and renal disease, which are often which are often associated with ARTassociated with ART, were , were greater in the treatment interruption arm.greater in the treatment interruption arm.

ACTG 5142ACTG 5142 Phase 3, randomized, open-label Phase 3, randomized, open-label

study comparing three regimens: study comparing three regimens: lopinavir/ritonavir + 2 NRTI; Efavirenz lopinavir/ritonavir + 2 NRTI; Efavirenz vs. 2 NRTI; lopinavir/ritonavir + vs. 2 NRTI; lopinavir/ritonavir + efavirenzefavirenz

753 ART-Naive patients with viral load 753 ART-Naive patients with viral load >2,000>2,000

NRTIs were chosen by clinicians and NRTIs were chosen by clinicians and patients; initially only one provided at patients; initially only one provided at no cost (extended-release no cost (extended-release stavudinestavudine…later tenofovir was added)…later tenofovir was added)

ACTG 5142ACTG 5142 Week 96Week 96

Proportion of patients with VL < 50 copies/mL Proportion of patients with VL < 50 copies/mL statistically significantly greater in Efavirenz statistically significantly greater in Efavirenz armarm

Median increase in CD4 count was significantly Median increase in CD4 count was significantly higher in the lopinavir armhigher in the lopinavir arm

Those patients in the NRTI-sparing arm had Those patients in the NRTI-sparing arm had significantly higher fasting triglyceride levels significantly higher fasting triglyceride levels (14% grade 3, compared to 6% in lopinavir (14% grade 3, compared to 6% in lopinavir arm, 3% in efavirenz arm); 45% moderate of arm, 3% in efavirenz arm); 45% moderate of severe laboratory abnormalitysevere laboratory abnormality

No resistance to lopinavir was observed; No resistance to lopinavir was observed; however, resistance to efavirenz was detected however, resistance to efavirenz was detected in nearly half of patients who failed this in nearly half of patients who failed this regimen; NRTI resistance was more common regimen; NRTI resistance was more common with virologic failure on efavirenz as well with virologic failure on efavirenz as well Riddler S. et al. New England Journal of Medicine, May 15, 2008.

VirologiVirologic c success success (%)(%)

RegimeRegimen n contin-contin-uationuation

<200 <200 copiescopies

<50 <50 copiescopies

CD4 CD4 increasincreasee

LopinavLopinavir/r + ir/r + efavirenefavirenzz

7373 6161 9292 8383 268268

LopinavLopinavir/r + 2 ir/r + 2 NRTINRTI

6767 5454 8686 7777 285285

EfavirenEfavirenz + 2 z + 2 NRTINRTI

7676 6060 9393 8989 241241

Riddler S, et al. 96 week data from ACTG 5142

TITANTITAN Phase 3 study comparing darunavir/r and Phase 3 study comparing darunavir/r and

lopinavir/r in patients with VL < 1000 lopinavir/r in patients with VL < 1000 copies/mL, on stable but failing regimen for copies/mL, on stable but failing regimen for at least 12 weeksat least 12 weeks

604 patients randomized to open label 604 patients randomized to open label lopinavir/r or darunavir/r, both with lopinavir/r or darunavir/r, both with optimized background selected based on optimized background selected based on resistance testing (T-20 and investigational resistance testing (T-20 and investigational drugs excluded)drugs excluded)

Previous lopinavir therapy exclusion criteriaPrevious lopinavir therapy exclusion criteria Data from week 48 present at IDSA 2007, Data from week 48 present at IDSA 2007,

San DiegoSan Diego

TITANTITAN Both PIs were well tolerated, only 7% Both PIs were well tolerated, only 7%

discontinued due to toxicitydiscontinued due to toxicity Lipid level elevation similar between the groups; Lipid level elevation similar between the groups;

higher incidence of diarrhea in lopinavir arm (42% higher incidence of diarrhea in lopinavir arm (42% vs. 32%), rash in darunavir arm (16% vs. 7%)vs. 32%), rash in darunavir arm (16% vs. 7%)

Significantly more patients in darunavir arm Significantly more patients in darunavir arm achieved VL <50; fewer patients in darunavir arm achieved VL <50; fewer patients in darunavir arm had virologic failure (10% vs 22%), and had had virologic failure (10% vs 22%), and had primary PI mutations (21% vs. 36%)primary PI mutations (21% vs. 36%)

**among patients with baseline lopinavir fold-**among patients with baseline lopinavir fold-change of greater than 10-fold, only 28% change of greater than 10-fold, only 28% achieved VL <50 (greater virologic failure driven achieved VL <50 (greater virologic failure driven by baseline phenotypic resistance to lopinavir??)by baseline phenotypic resistance to lopinavir??)

DRV/rDRV/r LPV/rLPV/r P valueP value

VL<50VL<50 7171 6060 0.0050.005

VL<400VL<400 7777 6767 <0.0001<0.0001

CD4 CD4 increaseincrease

8888 6161 0.330.33

Adapted from Hardy WD et al. IDSA 2007; San Diego, CA. Abstract 1209.

TITAN – 48 weeks efficacy results

Newly available ARVsNewly available ARVs

MERITMERIT MOTIVATEMOTIVATE BENCHMRKBENCHMRK MERCK 004MERCK 004

Integrase cross-resistanceIntegrase cross-resistance Effects on lipid parametersEffects on lipid parameters

DUETDUET

MERIT: Maraviroc vs Efavirenz in MERIT: Maraviroc vs Efavirenz in Treatment-Naive PatientsTreatment-Naive Patients

Antiretroviral-naive patients infected with

CCR5-tropic HIV-1 and HIV-1 RNA

2000 copies/mL

(N = 740)

MVC 300 mg twice daily + ZDV/3TC(n = 360)

EFV 600 mg once daily + ZDV/3TC(n = 361)

Week 48 primary endpoint

Stratified by HIV-1 RNA < or 100,000 copies/mL and by Northern or Southern

Hemisphere

MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at end of phase IIB (Week 16)

Week 96

Saag M, et al. IAS 2007. Abstract WESS104.

Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CI

MERIT: Patients With VL < 50 MERIT: Patients With VL < 50 Copies/mL by baseline VL Copies/mL by baseline VL

71.6 69.6 66.659.6

Pat

ien

ts,

%

BL VL < 100,000 copies/mL

BL VL ≥ 100,000 copies/mL

0

10

20

30

40

50

60

70

80

90

100

n =

211 204

150 156

MVCEFV

Saag M, et al. IAS 2007. Abstract WESS104.

EFV patients more likely to discontinue due to AE

– Overall : 25.2%

– AE: 13.6%

– Efficacy: 4.2%

MVC patients more likely to discontinue due to lack of efficacy

– Overall: 26.9%

– AE: 4.2%

– Efficacy: 11.9%

MOTIVATE: Maraviroc in Treatment-MOTIVATE: Maraviroc in Treatment-Experienced Patients With R5 VirusExperienced Patients With R5 Virus

Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.

*Patients receiving PI (other than TPV) or DLV received 150 mg; all others received 300 mg. †OBR: 3-6 ARVs.

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)

Placebo + OBR†

MVC 150 mg or 300 mg* once daily + OBR†

MVC 150 mg or 300 mg* twice daily + OBR†

2:2:1 randomization;stratified by ENF use and VL

Week 24 planned interim analysis Week 48

Randomized, double-blind, placebo-controlled, parallel phase IIb/III studiesRandomized, double-blind, placebo-controlled, parallel phase IIb/III studies 44% failed screening with X4 or dual/mixed virus detected44% failed screening with X4 or dual/mixed virus detected Primary endpoint: mean change in HIV-1 RNA at Week 24Primary endpoint: mean change in HIV-1 RNA at Week 24 Based on MOTIVATE data FDA approved MVC in August 2007 for use in treatment-Based on MOTIVATE data FDA approved MVC in August 2007 for use in treatment-

experienced patients with R5-tropic virus onlyexperienced patients with R5-tropic virus only

MOTIVATE 1 and 2: Combined MOTIVATE 1 and 2: Combined Virologic and Immunologic EfficacyVirologic and Immunologic Efficacy

*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.

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

Gulick RM, et al. IAS 2007. Abstract WEPEB116LB.

OutcomeOutcome Placebo+ Placebo+ OBROBR

MVC QD + MVC QD + OBROBR

MVCMVC

BID + OBRBID + OBR

VL<400VL<400 2828 5555‡‡ 6161‡‡

VL<50VL<50 2323 4444‡‡ 4545‡‡

Mean CD4 increaseMean CD4 increase 5757 109109 106106

Maraviroc dosingMaraviroc dosing With CYP3A inhibitors: 150 mg po BIDWith CYP3A inhibitors: 150 mg po BID

PIs (except tipranavir)PIs (except tipranavir) Ketoconzale, itraconazole, clarithromycinKetoconzale, itraconazole, clarithromycin

With NRTIs, nevirapine, tipranavir / With NRTIs, nevirapine, tipranavir / ritonavir,enfuvirtide: 300 mg po BID ritonavir,enfuvirtide: 300 mg po BID (recommended dose)(recommended dose)

With CYP3A inducers: 600 mg (2 tabs) po With CYP3A inducers: 600 mg (2 tabs) po BIDBID EfavirenzEfavirenz RifampinRifampin CarbamazepineCarbamazepine PhenytoinPhenytoin phenobarbitalphenobarbital

Tropism testingTropism testing

““Trofile”: co-Trofile”: co-receptor tropism receptor tropism assay - detects R5 assay - detects R5 vs. X4 virusvs. X4 virus Monogram Monogram

biosciencesbiosciences HIV RNA > 1000 HIV RNA > 1000

copies/mL requiredcopies/mL required

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

Viral dynamics substudy: second-phase decay may be accelerated with RAL[2]

Markowitz M, et al. IAS 2007. Abstract TUAB104. 2. Murray JM, et al. IAS 2007. Abstract TUAB103.

Patient Patient Outcome, %Outcome, %

RAL 100 RAL 100 mg (n = mg (n =

39)39)

RAL 200 RAL 200 mgmg

(n = 40)(n = 40)

RAL 400 RAL 400 mg mg

(n = 41)(n = 41)

RAL 600 RAL 600 mg mg

(n = 40)(n = 40)

EFV 600 EFV 600 mgmg

(n = 38)(n = 38)

VL < 400 VL < 400 copies/mLcopies/mL Week 24Week 24 9595 8585 9898 9595 9595 Week 48Week 48 9797 8585 9898 9090 8787

VL < 50 VL < 50 copies/mLcopies/mL Week 24Week 24 8787 8585 9393 9595 9292 Week 48Week 48 8585 8383 8888 8888 8787

Protocol 004: Raltegravir vs Protocol 004: Raltegravir vs Efavirenz in Treatment-Naive Efavirenz in Treatment-Naive

PatientsPatients

Protocol 004: RAL Associated With Protocol 004: RAL Associated With Fewer Lipid Effects vs EFVFewer Lipid Effects vs EFV

RAL well tolerated with no dose-related toxicitiesRAL well tolerated with no dose-related toxicities Dizziness, headache, and atypical dreams more frequent with Dizziness, headache, and atypical dreams more frequent with

EFVEFV

Total cholesterol, LDL-cholesterol, triglycerides not Total cholesterol, LDL-cholesterol, triglycerides not increased by RALincreased by RAL

*All RAL dose groups combined.

Markowitz M, et al. IAS 2007. Abstract TUAB104.

Mean change Mean change from from baseline, baseline, mg/Lmg/L

RAL 100-RAL 100-600mg BID600mg BID

EFV 600mg EFV 600mg QDQD

P valueP value

Total cholTotal chol -2.3 -2.3 +20.7+20.7 <0.001<0.001

LDLLDL -7.5-7.5 +3.0+3.0 0.0160.016

TGTG -1.0-1.0 +49.5+49.5 0.0680.068

BENCHMRKBENCHMRK

Double blind clinical trial: pts assigned to 200, Double blind clinical trial: pts assigned to 200, 400 or 600 mg of MK-0518 BID along with OBT or 400 or 600 mg of MK-0518 BID along with OBT or placebo with OBTplacebo with OBT

178 patients with at least one resistance 178 patients with at least one resistance mutation in each of 3 drug classes, VL > 5,000, mutation in each of 3 drug classes, VL > 5,000, CD4 above 50CD4 above 50

14% placebo group achieved VL<50 by week 2414% placebo group achieved VL<50 by week 24 65, 57, 67% achieved VL<50 taking 3 doses of 65, 57, 67% achieved VL<50 taking 3 doses of

MK-0518MK-0518 Co-administration of T-20 boosted responses by Co-administration of T-20 boosted responses by

about 20% in the MK-0518 armsabout 20% in the MK-0518 arms

BENCHMRK 1 and 2: Raltegravir BENCHMRK 1 and 2: Raltegravir (MK-0518) in Treatment-(MK-0518) in Treatment-

Experienced PtsExperienced Pts

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.

Raltegravir 400 mg twice daily + OBR*BENCHMRK-1 (n = 232)BENCHMRK-2 (n = 230)

Placebo + OBR*BENCHMRK-1 (n = 118)BENCHMRK-2 (n = 119)

HIV-infected,triple-class resistant,

HIV-1 RNA > 1000 copies/mL

BENCHMRK-1 (N = 350)(Europe, Asia/Pacific, Peru)

BENCHMRK-2 (N = 349)(North, South America)

*Selected investigational antiretrovirals permitted in OBR.

Primary endpoints:

Week 16

Planned duration: Week 48

Randomized, double-blind, placebo-controlled, parallel phase III studies

Primary endpoints: HIV-1 RNA, CD4+ cell counts, and adverse events at Week 16

BENCHMRK 1 and 2: BENCHMRK 1 and 2: VL < 400 copies/mL (ITT, NC = F)VL < 400 copies/mL (ITT, NC = F)

Weeks

Pat

ien

ts W

ith

HIV

-1 R

NA

<

400

co

pie

s/m

L (

%)

P < .001 at Week 16 P < .001 at Week 16

Weeks0 2 4 8 12 16 24

0

20

40

60

80

100

0 2 4 8 12 16 240

20

40

60

80

100 BENCHMRK-2BENCHMRK-1

Raltegravir + OBR Placebo + OBR

77%

41%

77%

43%

230

81

158

118

232

118

n =

n =

229

69

128

119

230

119

n =

n =Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.

BENCHMRK 1 and 2: BENCHMRK 1 and 2: VL < 50 copies/mL (ITT, NC = F)VL < 50 copies/mL (ITT, NC = F)

Raltegravir + OBR Placebo + OBR

P < .001 at Week 16

Pat

ien

ts w

ith

HIV

-1 R

NA

<

50

cop

ies/

mL

(%

)

P < .001 at Week 16

61%

33%

62%

36%

Weeks Weeks0 2 4 8 12 16 24 0 2 4 8 12 16 24

BENCHMRK-2BENCHMRK-1

230

81

158

118

232

118

n =

n =

229

69

128

119

230

119

n =

n =

0

20

40

60

80

100

0

20

40

60

80

100

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.

BENCHMRK 1 and 2: VL < 400 c/mL BENCHMRK 1 and 2: VL < 400 c/mL at Wk 16 by Specific Agents in OBRat Wk 16 by Specific Agents in OBR

+ : First use in OBR– : No use in OBR

Overall Efficacy Data

––

0 20 40 60 80 100

n

447230

Efficacy by Agents in OBR

Enfuvirtide Darunavir

+

+

+

+

–

–

879844

23

639042

24

559080

47

2974191

90

7943

Raltegravir + OBR

Placebo + OBR

Patients (%)Statistical analysis: virologic failure carried forward.

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.

Raltegravir and ?malignanciesRaltegravir and ?malignancies Malignancy ConclusionsMalignancy Conclusions

• In the original application, an imbalance in rates of malignancies • In the original application, an imbalance in rates of malignancies was noted. The malignancy types and rates in the raltegravir was noted. The malignancy types and rates in the raltegravir group are those anticipated in a severely immunodeficient group are those anticipated in a severely immunodeficient HIV/AIDS population and are consistent with reported rates in the HIV/AIDS population and are consistent with reported rates in the literature. A history of malignancy prior to enrollment was literature. A history of malignancy prior to enrollment was common and many of the malignancies in the raltegravir group common and many of the malignancies in the raltegravir group were likely present at time of study entry or were recurrences of were likely present at time of study entry or were recurrences of prior diagnosed malignancies.prior diagnosed malignancies.• Based on an updated analysis of the same study cohorts, the • Based on an updated analysis of the same study cohorts, the imbalance in rates of malignancies has not been sustained with imbalance in rates of malignancies has not been sustained with additional follow-up. This is consistent with the possibility that the additional follow-up. This is consistent with the possibility that the original imbalance was a function of small numbers of cases and original imbalance was a function of small numbers of cases and relatively imprecise estimates of rates.relatively imprecise estimates of rates.• While the updated analysis is reassuring, the total amount of • While the updated analysis is reassuring, the total amount of safety follow-up is limited and additional data are needed. Further safety follow-up is limited and additional data are needed. Further follow-up is proposed in the Risk Management Plan.follow-up is proposed in the Risk Management Plan.  

Excerpted from Merck Briefing Document for FDA Hearing Sept 5, 2007

Raltegravir and malignancyRaltegravir and malignancy

".....Overall, the rates and kinds of malignancies seen in ".....Overall, the rates and kinds of malignancies seen in patients receiving raltegravir in the clinical development patients receiving raltegravir in the clinical development program approximate the rates and kinds of malignancies program approximate the rates and kinds of malignancies reported in the literature for patients with HIV/AIDS....reported in the literature for patients with HIV/AIDS....  ....It is also noteworthy that in the patients receiving ....It is also noteworthy that in the patients receiving raltegravir who ultimately developed a malignancy, the raltegravir who ultimately developed a malignancy, the median CD4 cell count was 122 cells/mm3 and all median CD4 cell count was 122 cells/mm3 and all patients with malignancy had a history of AIDS, a known patients with malignancy had a history of AIDS, a known independent risk factor for malignancy. Most of the independent risk factor for malignancy. Most of the malignancies encountered are associated with well known malignancies encountered are associated with well known risk factors for malignancy such as AIDS, oncogenic risk factors for malignancy such as AIDS, oncogenic viruses (papillomavirus infection, hepatitis B virus viruses (papillomavirus infection, hepatitis B virus infection), and tobacco. 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 19Kaplan-Meier Plot of Time to Malignancy-Double-Blind PhasePhase II and III StudiesOriginal 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 20Kaplan-Meier Plot of Time to Malignancy-Double-Blind PhasePhase II and III StudiesCumulative Update as of 09-Jul-2007Note: These data have not been reviewed by the FDA.

Integrase Inhibitor Resistance and Integrase Inhibitor Resistance and Cross-ResistanceCross-Resistance

Protocol 004: VF in 5 RAL recipients (3%)Protocol 004: VF in 5 RAL recipients (3%) 3 had no detected integrase mutations3 had no detected integrase mutations 1 had N155H + M184M/I/V1 had N155H + M184M/I/V 1 had N155H + other mutations (V151I, D232D/N, G163G/R)1 had N155H + other mutations (V151I, D232D/N, G163G/R)

Separate report of 2 patients with VF on elvitegravir Separate report of 2 patients with VF on elvitegravir (EVG)/RTV, with no VL response during first week after (EVG)/RTV, with no VL response during first week after switch to RALswitch to RAL Suggests high level of cross-resistance between first 2 integrase Suggests high level of cross-resistance between first 2 integrase

inhibitorsinhibitors Patient 1 had N155H and 3 other integrase mutations at VF (VL: Patient 1 had N155H and 3 other integrase mutations at VF (VL:

840 copies/mL) on EVG/RTV840 copies/mL) on EVG/RTV Regained viral suppression (< 50 copies/mL) after addition of DRV/RTV to RALRegained viral suppression (< 50 copies/mL) after addition of DRV/RTV to RAL

Patient 2 had Q148R and 4 other integrase mutations at VF (VL: Patient 2 had Q148R and 4 other integrase mutations at VF (VL: 10,700 copies/mL) on EVG/RTV 10,700 copies/mL) on EVG/RTV

Failed to regain suppression after addition of DRV/RTV to RALFailed 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 .

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

(DUET-1: N = 612 DUET-2: N = 591)

Placebo+ DRV/RTV-containing OBR†

ETR 200 mg BID*

+ DRV/RTV-containing OBR†

Week 48

*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)

Week 24‡

DUET-1 and -2: Etravirine + DRV/RTV-Containing OBR Phase III Trials

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: Virologic Response DUET-1 and -2: Virologic Response at Week 24 (TLOVR Analysis)at Week 24 (TLOVR Analysis)

0P ETRP ETR

20

40

60

80

100

44%

62%

39%

56%

DUET-1 DUET-2

VL

< 5

0 co

pie

s/m

L, %

Placebo

ETR

P = .005P = .0003

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 DUET-1 and -2: BL ETR Mutations and Virologic Response at Week 24and Virologic Response at Week 24

0 1 2 3

Pat

ien

ts W

ith

HIV

-1

RN

A <

50

cop

ies/

mL

(%

)

0

102030

4050607080

90100

4 5

No. of BL ETR Mutations

Patients (%) 40 30 16 8 5 1

13 mutations associated with ETR resistanceV90I A98GL100I K101E/P V106I V179D/FY181C/I/V 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

– 14% of patients had ≥ 3 ETR resistance mutations at BL

Katlama C, et al. IAS 2007. Abstract WESS204.2.

Investigational ARVsInvestigational ARVs

Vicriviroc – ACTG 5211Vicriviroc – ACTG 5211

ElvitegravirElvitegravir

CCR5 monoclonal antibody – PRO 140CCR5 monoclonal antibody – PRO 140

othersothers

ACTG 5211: Phase II Trial of ACTG 5211: Phase II Trial of Vicriviroc in Treatment-Experienced Vicriviroc in Treatment-Experienced

PatientsPatients

Gulick R, et al. J Infect Dis 2007;196:304-312.

OBR (includes 100-800 mg Ritonavir)

Placebo(n = 28)

Vicriviroc 5 mg once daily(n = 30)

Vicriviroc 10 mg once daily(n = 30)

Vicriviroc 15 mg once daily(n = 30)

Antiretroviral-experienced Antiretroviral-experienced patients with HIV-1 RNA ≥ patients with HIV-1 RNA ≥

5000 copies/mL and R5-only 5000 copies/mL and R5-only virus on ritonavir-containing virus on ritonavir-containing

regimen regimen

(N = 118)(N = 118)

Failing regimen

Day 14 Week 48Stratified by enfuvirtide use and

baseline CD4+ count < or ≥ 50 cells/mm³

Discontinued

0

30

60

100

Pat

ien

ts, %

7

27

Week 24

40

10

20

40

50

70

80

90

11

27

Week 48

37

Placebo Vicriviroc 10 mg Vicriviroc 15 mg

ACTG 5211: Patients with HIV-1 RNA < 50 copies/mL at 24 and 48 Weeks

VCV + RTV-containing OBR associated VCV + RTV-containing OBR associated with sustained antiviral activity at with sustained antiviral activity at Week 48Week 48

Gulick R, et al. J Infect Dis 2007;196:304-312.

ACTG 5211: Safety, Tolerability, ACTG 5211: Safety, Tolerability, and Tropism on Failureand Tropism on Failure

Incidence of grade 3/4 AEs comparable among arms Incidence of grade 3/4 AEs comparable among arms ((PP ≥ .6) ≥ .6)

10 patients developed malignancies (4 additional 10 patients developed malignancies (4 additional patients since Week 24)patients since Week 24) Vicriviroc: 8 patients Vicriviroc: 8 patients

Non-Hodgkin’s lymphoma: n = 2Non-Hodgkin’s lymphoma: n = 2 –– Hodgkin’s disease: n = 2Hodgkin’s disease: n = 2 Gastric adenocarcinoma: n = 1Gastric adenocarcinoma: n = 1 –– Squamous cell carcinoma: Squamous cell carcinoma:

n = 1n = 1 Basal cell carcinoma: n = 1Basal cell carcinoma: n = 1 –– Kaposi sarcoma recurrence: n = 1Kaposi sarcoma recurrence: n = 1

Placebo: 2 patientsPlacebo: 2 patients Squamous cell carcinoma: n = 2Squamous cell carcinoma: n = 2

9 (35%) of 26 patients with VF on vicriviroc had 9 (35%) of 26 patients with VF on vicriviroc had dual/mixed or X4 virus detecteddual/mixed or X4 virus detected

Gulick R, et al. J Infect Dis 2007;196:304-312.

PRO 140 1302: Effects of a Single PRO 140 1302: Effects of a Single IV Humanized CCR5 Antibody IV Humanized CCR5 Antibody

InfusionInfusion

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

(N = 39)

PRO 140 0.5 mg/kg single IV infusion(n = 10)

PRO 140 2.0 mg/kg single IV infusion(n = 10)

PRO 140 5.0 mg/kg single IV infusion(n = 10)

Placebo(n = 9)

59-day follow-up

Saag MS, et al. IAS 2007. Abstract WESS201.

‡‡

‡

‡

‡ ‡†† *

0 10 20 30 40 50 60Study Day

-2.0

-1.5

-1.0

-0.5

0.0

0.5

Me

an

Ch

an

ge

in

VL

, lo

g10

co

pie

s/m

L

*P ≤ .01†P ≤ .001‡P ≤ .0001

Placebo 0.5 mg/kg 2 mg/kg 5 mg/kg

The HLA-B*5701 genotype has The HLA-B*5701 genotype has been shown to be a predictive risk been shown to be a predictive risk

factor forfactor for

A) p

oor C

D4+ c

ell r

e...

B) A

BC hyp

erse

nsitiv

ity

C) i

nsulin

resi

stan

ce

D) l

ipoat

rophy

0% 0%0%0%

A) poor CD4+ cell A) poor CD4+ cell responseresponse

B) ABC B) ABC hypersensitivityhypersensitivity

C) insulin C) insulin resistanceresistance

D) lipoatrophyD) lipoatrophy20

New testing availableNew testing available

HLA-B*5701 testing for Abacavir HLA-B*5701 testing for Abacavir hypersensitivity (HSR) – LabCorp, Quest; hypersensitivity (HSR) – LabCorp, Quest; PCR on whole blood or buccal swab to PCR on whole blood or buccal swab to determine presence of HLA-B5701 alleledetermine presence of HLA-B5701 allele HSR observed in about 5% of patients in HSR observed in about 5% of patients in

clinical trials; 89% of cases occur in the clinical trials; 89% of cases occur in the first 6 weeks of therapy with ABCfirst 6 weeks of therapy with ABC

Most have multiple symptoms (fever, Most have multiple symptoms (fever, rash, myalgias, arthralgias, etc…)rash, myalgias, arthralgias, etc…)

Ziagen package insert; GSK 2003; J Antimicrob Chemother. 2007; 59:591-593.

CASES CONTROLS

Black and white subjects with clinically suspected

ABC HSR (CS-HSR)

SHAPE: Retrospective Case-Control SHAPE: Retrospective Case-Control StudyStudy

White: n = 130Black: n = 69

White: n = 42Black: n = 5

White: n = 85Black: n = 63

White: n = 202Black: n = 206

Black and white subjects enrolled in KLEAN, ALOHA,

CNA30027, CNA30032

ABCskin patch test

and HLA-B*5701

Identify ABC-tolerantsubjects

Skin patch test positive

Skin patch test negative

Clinical Infectious Diseases. Volume 46, Issue 7, Page 1111–1118, Apr 2008 .

SHAPE: Sensitivity and Specificity of HLA-B*5701

0

30

60

100

Sen

siti

vity

/Sp

ecif

icit

y o

f H

LA

-B*5

701

, %

CS-HSR Skin Test Positive

44%

96%100%

10

20

40

50

70

80

90

White

CS-HSR

14%

99%100%

Black

Control Control

57/130 42/42 194/202 10/69 5/5 204/206

Skin Test Positive

Clinical Infectious Diseases. Volume 46, Issue 7, Page 1111–1118, Apr 2008

CS-HSR confirmed by HLA-B*5701 Sensitivity of HLA-B*5701 Specificity of HLA-B*5701

Case 1Case 1

46 year old male diagnosed in 2004; 46 year old male diagnosed in 2004; initial CD4 400 cells/mminitial CD4 400 cells/mm33; VL 55,000 ; VL 55,000 copies/mLcopies/mL

2 years later CD4 decreased to 230, VL 2 years later CD4 decreased to 230, VL increased to 150,000, and the patient increased to 150,000, and the patient opts to begin ART:opts to begin ART: Tenofovir / emtricitabineTenofovir / emtricitabine Atazanavir 300mg + Ritonavir 100 mgAtazanavir 300mg + Ritonavir 100 mg

After 6 months his CD4 is 450, VL <50After 6 months his CD4 is 450, VL <50

Case 1Case 1

The patient reports good tolerance of The patient reports good tolerance of regimen and overall good health; he regimen and overall good health; he uses loratadine and pseudoephedrine uses loratadine and pseudoephedrine for occasional bouts of seasonal for occasional bouts of seasonal rhinitis / sinusitisrhinitis / sinusitis

He also reports occasional overeating He also reports occasional overeating and binge drinking, accompanied by and binge drinking, accompanied by rare episodes of heartburn rare episodes of heartburn

Case 1Case 1

A few months later after having A few months later after having missed a regular quarterly visit, the missed a regular quarterly visit, the patient’s CD4 is 290 and VL 27,500; patient’s CD4 is 290 and VL 27,500; repeat testing confirmsrepeat testing confirms

On questioning the patient reveals On questioning the patient reveals having missed occasional doses of having missed occasional doses of ritonavir, in an attempt to reduce ritonavir, in an attempt to reduce diarrhea and bloating, and having diarrhea and bloating, and having initiated over the counter initiated over the counter omeprazole nearly daily, 20-40 mgomeprazole nearly daily, 20-40 mg

In addition to reinforcing the importance of In addition to reinforcing the importance of adherance to ritonavir, as well as the other adherance to ritonavir, as well as the other drugs in his ARV regimen, what next steps drugs in his ARV regimen, what next steps

would you take?would you take?

A) a

dvis

e th

e pat

ient

..

B) a

dvis

e to

dis

conti.

..

C) a

dvis

e to

dis

conti.

..

0% 0%0%

A) advise the patient to A) advise the patient to avoid omeprazole avoid omeprazole within 12 hours of within 12 hours of taking atazanavirtaking atazanavir

B) advise to discontinue B) advise to discontinue atazanavir and atazanavir and intensify the regimen, intensify the regimen, increasing the dose to increasing the dose to 400 mg /day400 mg /day

C) advise to discontinue C) advise to discontinue omeprazole and order omeprazole and order resistance testingresistance testing

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Genotype reveals the following mutations:Genotype reveals the following mutations:RT: K65R, M184V, G190ART: K65R, M184V, G190A

PI: I50L, G73SPI: I50L, G73SWhich regimen would you choose at this Which regimen would you choose at this

juncture?juncture?

A) n

ew b

oosted

PI +

...

B) n

ew b

oosted

PI +

...

C) N

NRTI plu

s NRTIs

0% 0%0%

A) new boosted PI + A) new boosted PI + NRTINRTI

B) new boosted PI + B) new boosted PI + NRTI plus NRTI plus enfuvirtideenfuvirtide

C) NNRTI plus NRTIsC) NNRTI plus NRTIs

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Case 1Case 1

Genotype reveals likely lack of susceptibility Genotype reveals likely lack of susceptibility to approved NNRTIs (G190A); although he to approved NNRTIs (G190A); although he has not been exposed to this class he may has not been exposed to this class he may have acquired the mutation at initial have acquired the mutation at initial infection or subsequent reinfectioninfection or subsequent reinfection

Use of a fusion inhibitor is unnecessary in Use of a fusion inhibitor is unnecessary in this case to construct a regimen with at this case to construct a regimen with at least 2, ideally 3 active agents; reserving least 2, ideally 3 active agents; reserving active agents for future use is an important active agents for future use is an important strategy in HIV management strategy in HIV management

Based on resistance mutations, which Based on resistance mutations, which combination would you choose? combination would you choose?

(M184V, K65R, G190A)(M184V, K65R, G190A)

A) T

enofo

vir +

em

trici

...

B) Z

idov

udine

+ lam

i...

C) A

bacav

ir +

lam

ivu...

D) S

tavu

dine

+ la

miv

...

0% 0%0%0%

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A) Tenofovir + A) Tenofovir + emtricitabineemtricitabine

B) Zidovudine + B) Zidovudine + lamivudinelamivudine

C) Abacavir + C) Abacavir + lamivudinelamivudine

D) Stavudine + D) Stavudine + lamivudinelamivudine

Case 1Case 1

Genotype pattern suggests susceptibility Genotype pattern suggests susceptibility to abacavir, didanosine, and tenofovir to abacavir, didanosine, and tenofovir would most likely be reducedwould most likely be reduced

The M184V may increase susceptibility to The M184V may increase susceptibility to zidovudine in the presence of 3TC or FTCzidovudine in the presence of 3TC or FTC

Stavudine likely remains phenotypically Stavudine likely remains phenotypically activeactive

Cased on recent clinical trial data, treatment Cased on recent clinical trial data, treatment history, and genotype, which boosted PI history, and genotype, which boosted PI

would you choose?would you choose?

A) F

osam

prenav

ir / r

...

B) L

opin

avir

/ rito

navi

r

C) D

arunav

ir / r

itonav

ir

0% 0%0%

A) Fosamprenavir / A) Fosamprenavir / ritonavirritonavir

B) Lopinavir / B) Lopinavir / ritonavirritonavir

C) Darunavir / C) Darunavir / ritonavirritonavir

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Case 1Case 1 All 3 choices are reasonable and have a All 3 choices are reasonable and have a

good likelihood of achieving undetectable good likelihood of achieving undetectable HIV-1 RNA; the patient has minimal PI HIV-1 RNA; the patient has minimal PI resistance (I50L confers resistance to resistance (I50L confers resistance to atazanavir, G73S confers broad PI atazanavir, G73S confers broad PI resistance, but likely would have little resistance, but likely would have little impact unaccompanied by another major PI impact unaccompanied by another major PI mutation)mutation)

Based on the results of TITAN, Based on the results of TITAN, darunavir/ritonavir out-performed darunavir/ritonavir out-performed lopinavir/ritonavir at 48 weeks in lopinavir/ritonavir at 48 weeks in lessless treatment-experienced patients (31% treatment-experienced patients (31% naïve, 38% had received 1 PI)naïve, 38% had received 1 PI)

Case 1Case 1 POWER-1 demonstrated the POWER-1 demonstrated the

superiority of darunavir/ritonavir over superiority of darunavir/ritonavir over investigator-selected comparator PIs investigator-selected comparator PIs in triple-class experienced patients in triple-class experienced patients (in combination with OBT)(in combination with OBT)

KLEAN and CONTEXT demonstrated KLEAN and CONTEXT demonstrated efficacy and noninferiority of boosted efficacy and noninferiority of boosted fosamprenavir in comparison with fosamprenavir in comparison with lopinavir/ritonavir, in both naïve and lopinavir/ritonavir, in both naïve and experienced patients, respectivelyexperienced patients, respectively

Case 2Case 2 50 year old male initially diagnosed in 1987, RF 50 year old male initially diagnosed in 1987, RF

MSM; initial CD4 800, nadir about 150. + history MSM; initial CD4 800, nadir about 150. + history of Kaposi’s sarcoma, recurrent molluscum, and of Kaposi’s sarcoma, recurrent molluscum, and esophageal candidiasisesophageal candidiasis

ART regimens:ART regimens: 1992-1995: zidovudine monotherapy; CD4 2411992-1995: zidovudine monotherapy; CD4 241 1995-1996: zidovudine + lamivudine; CD4 327, VL 100K1995-1996: zidovudine + lamivudine; CD4 327, VL 100K 1996-1998: zidovudine + lamivudine + indinavir; CD4 1996-1998: zidovudine + lamivudine + indinavir; CD4

708708 1998-2003: didanosine+ ritonavir + saquinavir; CD4 1998-2003: didanosine+ ritonavir + saquinavir; CD4

580, VL 236K580, VL 236K 2003-2004: lamivudine + didanosine + lopinavir / 2003-2004: lamivudine + didanosine + lopinavir /

ritonavir; CD4 336, VL 111 Kritonavir; CD4 336, VL 111 K Diagnosed with acute HBV infection, +sAg and eAgDiagnosed with acute HBV infection, +sAg and eAg

Case 2Case 2

In 2004, virtual phenotype/genotype In 2004, virtual phenotype/genotype shows: shows: RT: M184V, 41L, 210W, 215YRT: M184V, 41L, 210W, 215Y PI: 54V, 71V, 82API: 54V, 71V, 82A Data for atazanavir and fosamprenavir Data for atazanavir and fosamprenavir

not yet availablenot yet available

Based on this resistance pattern and the Based on this resistance pattern and the patient’s history, what regimen would you patient’s history, what regimen would you

choose at this juncture?choose at this juncture?

A) Z

idov

udine

/ lam

iv...

B) T

enofo

vir /

em

trici

...

C) T

enofo

vir /

em

trici

...

D) T

enofo

vir /

em

trici

...

0% 0%0%0%

A) Zidovudine / A) Zidovudine / lamivudine + lopinavir lamivudine + lopinavir / ritonavir/ ritonavir

B) Tenofovir / B) Tenofovir / emtricitabine + emtricitabine + nevirapinenevirapine

C) Tenofovir / C) Tenofovir / emtricitabine + emtricitabine + stavudine + efavirenzstavudine + efavirenz

D) Tenofovir / D) Tenofovir / emtricitabine + emtricitabine + efavirenz + efavirenz + fosamprenavir + fosamprenavir + ritonavirritonavir

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Case 2Case 2

He begins new regimen of tenofovir and He begins new regimen of tenofovir and FTC, + boosted fosamprenavir, + FTC, + boosted fosamprenavir, + efavirenz: CD4 >600; VL <400 efavirenz: CD4 >600; VL <400 consistently for > 1 year.consistently for > 1 year.

The patient requests regimen The patient requests regimen simplification in 1/07 due to pill burden simplification in 1/07 due to pill burden and fatigue, GI side effects, and and fatigue, GI side effects, and lipodystrophy. He attempts to enroll in a lipodystrophy. He attempts to enroll in a local clinial trial examining the role of local clinial trial examining the role of rosiglitazone in HIV-related lipodystrophy.rosiglitazone in HIV-related lipodystrophy.

What do you recommend What do you recommend now?now?

A) r

efuse

a c

hange

in...

B) a

gree

to g

ive

the

p...

C) c

hange

the

regi

m..

0% 0%0%

A) refuse a change in A) refuse a change in regimen, reinforce the regimen, reinforce the importance of complianceimportance of compliance

B) agree to give the patient a B) agree to give the patient a “drug holiday” “drug holiday” (structured treatment (structured treatment interruption)interruption)

C) change the regimen to C) change the regimen to tenofovir / emtricitabine / tenofovir / emtricitabine / efavirenz, which has just efavirenz, which has just become availablebecome available

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Case 2Case 2

The patient begins tenofovir / The patient begins tenofovir / emtricitabine / efavirenz.emtricitabine / efavirenz.

3 months later he feels great, is 3 months later he feels great, is tolerating the drug extremely well, tolerating the drug extremely well, and his CD4 count is still 708 (35%)…and his CD4 count is still 708 (35%)…

BUT…his viral load has climbed to BUT…his viral load has climbed to 6437…now what?6437…now what?

A) continue his current regimen…the A) continue his current regimen…the viral load was probably a “blip” and viral load was probably a “blip” and will come back down.will come back down.

B) restart fosamprenavir and B) restart fosamprenavir and ritonavir.ritonavir.

C) repeat the viral load and order C) repeat the viral load and order resistance testing with plans to resistance testing with plans to completely change his regimen.completely change his regimen.

Case 2Case 2

Genotype/virtual phenotype performed Genotype/virtual phenotype performed in April 2007 reveals the same NRTI in April 2007 reveals the same NRTI mutations as previously (M184V and mutations as previously (M184V and multiple TAMs); he now has the K103N, multiple TAMs); he now has the K103N, and the same PI mutations as he had in and the same PI mutations as he had in 2003, with phenotypic sensitivity only 2003, with phenotypic sensitivity only to saquinavir, tipranavir, and darunavir.to saquinavir, tipranavir, and darunavir.

What happened? What happened?

A) although he reported 100% A) although he reported 100% compliance, he probably missed doses compliance, he probably missed doses and developed resistance to the NNRTIsand developed resistance to the NNRTIs

B) the lack of three fully active drugs B) the lack of three fully active drugs put more selection pressure on put more selection pressure on efavirenz, bringing out an archived virus efavirenz, bringing out an archived virus with the K103N mutation, which he with the K103N mutation, which he acquired either at initial infection or acquired either at initial infection or later by reinfectionlater by reinfection

C) the geno/pheno from 2003 used a C) the geno/pheno from 2003 used a different technique and was therefore different technique and was therefore probably wrongprobably wrong

Case 2Case 2 The patient is concerned about his viral The patient is concerned about his viral

rebound, and is willing to begin a new rebound, and is willing to begin a new regimen. Based on most recent geno/pheno regimen. Based on most recent geno/pheno the patient begins tenofovir/emtricitabine, the patient begins tenofovir/emtricitabine, stavudine, darunavir, and ritonavir. His stavudine, darunavir, and ritonavir. His regimen now contains 3 drugs active against regimen now contains 3 drugs active against HIV and 2 active against hepatitis B.HIV and 2 active against hepatitis B.

Although he is tolerating the regimen well, Although he is tolerating the regimen well, and his viral load became undetectable after and his viral load became undetectable after 6 weeks (CD4 still about 700), he is now 6 weeks (CD4 still about 700), he is now concerned about increasing abdominal girth concerned about increasing abdominal girth and wasting of the extremities, which has and wasting of the extremities, which has been a chronic problem, but he’s noticed it been a chronic problem, but he’s noticed it even more since initiating the new regimen.even more since initiating the new regimen.

What might be a reasonable option for What might be a reasonable option for this patient in the near future, assuming this patient in the near future, assuming

his viral load remains undetectable?his viral load remains undetectable?

A) a

dd e

nfuvi

rtide

to h

..

B) s

ubst

itute

mar

avir.

.

C) s

ubst

itute

ralte

grav.

.

0% 0%0%

A) add enfuvirtide to his A) add enfuvirtide to his current regimencurrent regimen

B) substitute maraviroc B) substitute maraviroc for darunavir / ritonavirfor darunavir / ritonavir

C) substitute raltegravir C) substitute raltegravir for stavudine, with the for stavudine, with the possibility of adding / possibility of adding / substituting etravirine substituting etravirine at a later dateat a later date

20