Prise en charge des patients en é chec

Prise en charge des patients en checPierre-Marie Girard

Hpital St Antoine&IMEA, Paris

Prise en charge des patients en checPrvenir les situations dchec dit avanc

Stratgies dattente ?:

Interruption complte

Interruption partielle

Foscarnet

Nouveaux Antirtroviraux:Classes existantes: NRTI, NNRTI, IP, Inhibiteurs de fusionNouvelles Classes: Inhibiteurs de CCR5, Inhibiteurs dattachement, Inhibiteurs dintgrase, Inhibiteurs de maturation

Resistance Mechanism: very similar to TB

Incidence ofresistance

Anti HIV activity

Drug selection

Low

Intermediate

High

Resistance is driven by ongoing viral replication on treatment

Drusano GL et al. J Infect Dis 1998; 178:360-367

N = 130 patients treated with indinavir monotherapy

Resistance is driven by ongoing viral replication on treatmentThis slide shows a Kaplan-Meier plot of the probability of susceptibility to indinavir* in a cohort of 130 patients who had received at least 22 weeks of treatment with indinavir monotherapy and had experienced an initial reduction in HIV RNA of at least at least 0.75 log10 copies/ml from baseline [1]. The x axis represents the number of days on treatment.The y axis shows the probability of susceptibility.The red line represents patients who had at least one HIV RNA measure undetectable.The blue line represents patients who had at least one HIV RNA measure detectable but < 500 copies/ml.The green line represents patients who had no HIV RNA measure < 500 copies/ml.In this last group the probability of remaining susceptible to indinavir declined rapidly over time. These data illustrate a fundamental but important point about HIV resistance: residual HIV replication on treatment drives resistance. HIV resistance develops because of the low fidelity of the HIV reverse transcriptase (RT) enzyme which makes random mistakes when converting viral RNA into proviral DNA. If one of these mistakes, or mutations, allows the virus that carries it to replicate more efficiently in the presence of drug then it will persist and outgrow virus that does not carry the mutation. A higher rate of viral replication in the presence of drug will lead to more frequent generation of mutations and more rapid outgrowth, or selection, of resistant variants. The probability of resistance developing and the speed at which resistance develops is proportional to the level of residual viral replication.

*Susceptibility was defined as a lack of sustained increase in HIV RNA by at least 0.75 log10 copies/ml from nadir.

Reference Drusano GL et al. J Infect Dis 1998; 178:360-367

Multi-class resistance also increases over time

N = 4 306 on first HAART regimen (57% NNRTI, 39% PI, 4% 3 NRTIs)Cumulative risk of virological failure at 6 years: 38%

Philips A, et al. AIDS 2005 19:487494

Multi-class resistance also increases over timeThis slide shows data from the same cohort study as the previous slide [1]. 4 306 patients at six HIV clinics in and around London (UK CHIC study group) who started antiretroviral treatment with two NRTIs plus an NNRTI (57%), a PI (boosted or un-boosted, 39%) or a third NRTI (4%). After six years of HAART the cumulative risk of virological failure was 38%.The previous slide showed that the proportion of patients with at least one resistance mutation increased steadily over time on HAART. This graph shows the cumulative risk of having detectable mutations to two (purple) or three (orange) classes of antiretroviral after 2, 4 and 6 years. The x axis shows the number of years after the start of treatment.The y axis shows the percent of patients (Kaplan-Meier estimates) with virus classified as resistant.This slide illustrates that not only does the overall risk of resistance increase with time on treatment (as shown in the previous slide) but that multi-class resistance is similarly proportional to treatment duration.

Additional informationMedian follow-up time was 3.1 years and 790 (19%) of patients were followed for > 5 years.Changes to the original regimen were frequent: Kaplan-Meier estimates for starting one or more new drugs within 2, 4 and 6 years were 48%, 69% and 80%, respectively.The estimated risk of detecting at least one major mutation was 10% by year 2, 20% by year 4 and 27% by year 6.1 057 (25%) patients experienced virological failure. Kaplan-Meier estimates for virological failure within 2, 4 and 6 years were 21%, 30% and 38%, respectively.

Reference Phillips A, et al. AIDS 2005 19:487494.

Une bonne nouvelle: confirmer.

Lincidence de la multi-rsistance tend diminuer

Objectifs du traitement des patients en multi checDeux situations

Au moins 2 ARV prsums efficace:

Obtenir lindtectabilit virale plasmatique

Un seul ARV prsum efficace:

Rduire significativement la charge virale (> 1 log)Tolrance et Contraintes acceptablesMaintenir les CD4Prvenir les vnements opportunistesEviter laccumulation de mutations





Foscarnet

Nouveaux Antirtroviraux:Classes existantes: NRTI, NNRTI, IP, Inhibiteurs de fusionNouvelles Classes: Inhibiteurs de CCR5, Inhibiteurs dattachement, Inhibiteurs dintgrase, Inhibiteurs de maturation

Impact du maintien dARV rput inefficace selon gnotype VIHEtude Observationnelle 3TC

Essai randomis 3TC (avec M184V)

Sous analyse essais Toro

clinicaloptions.com/hiv

Update From the 2006 International AIDS Conference

3TC Monotherapy vs TI: Predictors of Response

Danise A, et al. IAC 2006. Abstract THPE0130.

Adjusted Hazard Ratios of Immunologic and Clinical Failure Estimated by Cox Proportional Hazard Regression Model

Type of Therapy (PI vs NNRTI vs NRTI)SexAge BL CD4+ (> 500 vs < 500)Nadir CD4+ (> 300 vs < 300)BL CD8+BL HIV RNA log10BL Number of MutationsTreatment (3TC vs TI)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

P = .0006

P = .028

P = .0025

For more information, go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Toronto%202006/Capsules/THPE0130.aspx?Track=Resistance

Interruption Partielle des ARV: Activit rsiduelle des INRT

Deeks SG, et al. JID 2005;192:1537-1544.

Deeks and coworkers evaluated changes in CD4+ cell counts and viral loads in a pilot study of MDR HIV-infected patients who interrupted either NRTIs only or PIs only. The investigators observed accelerated CD4+ cell count declines and increased viral loads, with the impact of discontinuing NRTIs being greater than the impact of discontinuing PIs.

For more information, please go online to:http://clinicaloptions.com/hiv/conf/croi2003/cs/640.asp

Foscarnet salvage therapy for patients with late-stage HIV disease and multiple drug resistance.

Etude piloteFoscarnet : induction 6 semaines la posologie de 5g x 2 /j ; si rponse S6 , poursuite 5 g x 2 /j sur 2 jours conscutifs par semaineCD4 < 100 /mm3Charge virale > 50 000 copies/mlHAART stable depuis 8 semaines 3 TAMS + 1 mutation NNRTI + 2 mutations majeures sur les IPZDV ou d4T dans rgime thrapeutiqueCanestri et al, Antiviral Therap, 2006

Foscarnet salvage therapy for patients with late-stage HIV disease and multiple drug resistanceCD4 : gain de 28 S6 , 60 S12ARN-VIH : rduction de 1.8 log S6 , 0.85 S12 Pas dapparition de nouvelles mutations sur NRTI ou IPAction par le biais dune probable hypersensibilit a la molcule chez les patients ayant des TAMS, + restauration de la sensibilit aux analogues de la thymidineRsultats similaires retrouvs par Mathiesen et al (AIDS 2004) : 1.8 log S2 Canestri et al, Antiviral Therap, 2006

Poursuite du traitement identique en cas dchec: un choix difficile

Maintien des mutationsBaisse fitnessRetarder progression

Risque accumulation des mutations et de resistance aux ARV en dveloppement

Making drug resistance work for HIV treatment requires a delicate balance. On the one hand, continuing therapy in the face of resistance may decrease viral RC and delay progression. On the other hand, continuing therapy may result in the accumulation of new mutationssuch as those observed with M184Vand development of resistance to drugs in development.

References:Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet. 1999;353:863-868. Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection.J Infect Dis. 2000;181:946-953.





Foscarnet

Nouveaux Antirtroviraux:Classes existantes: NRTI, NNRTI, IP, Inhibiteurs de fusion

Nouvelles Classes: Inhibiteurs de CCR5, Inhibiteurs dattachement, Inhibiteurs dintgrase, Inhibiteurs de maturation

Antirtroviraux potentiellement actifs en situation dchec chez des patients dits multitraits (i.e. VIH multimut)Enfuvirtide,CCR5 inhibitors, TNXTipranavirDarunavir, GSKNew NRTITMC125 (NNRTI)TMC278PA-457MK-0518GS-9137

TORO: Virologic Response to Enfuvirtide + OB Regimen

Arasth K, et al. IAC 2004. Abstract MoOrB1058.

ENF, enfuvirtide; ITT: DC or SW = F, intent-to-treat: discontinuation or switch equals failure analysis; OB, optimized background

These data are from the 96-week follow-up of the TORO trials. These were the pivotal studies that showed the efficacy of enfuvirtide when combined with an optimized background regimen in highly treatment-experienced patients. As had previously been shown, patients who received enfuvirtide plus an optimized background regimen had substantially greater reductions in plasma HIV RNA over the course of the first 24 weeks of the study, which was the primary endpoint, and a greater proportion of those patients achieved an undetectable viral load compared with the control arm, which was the secondary endpoint. At 96 weeks of follow-up patients in the control arm ceased participating in the study or all crossed over to receive enfuvirtide after 48 weeks, so there is no comparator arm for the next 48 weeks of the study. In essence, the 96-week data showed that the majority of the patients who were suppressed at Week 48 remained suppressed at Week 96. This was true whether looking at the < 400 copies/mL endpoint or the < 50 copies/mL endpoint, with 26% and 17% patients achieving suppression below these thresholds, respectively.

In addition, patients who had achieved a CD4+ cell count increase of at least 100 cells/mm3 were likely to retain that response. Approximately 38% of patients in the enfuvirtide arm had an increase of 100 cells/mm3 at Week 48, and 31% at Week 96. One interesting point is that there was no increase in the incidence of pneumonia observed during Weeks 48-96 of follow-up. This is important because it had been reported during the initial analysis of the study that patients in the enfuvirtide arm were significantly more likely to experience bacterial pneumonia compared with the control arm. In fact, the control arm patients had a much lower incidence of pneumonia than expected in comparable patient populations, whereas the incidence of pneumonia in the enfuvirtide arm was similar to that of matched controls in other cohorts. It is encouraging that there was not an additional increase in pneumonia during the subsequent 48 weeks, suggesting that this imbalance in pneumonia incidence is not due to cumulative exposure to enfuvirtide.

For more information, please go online to: http://clinicaloptions.com/HIV/Conference%20Coverage/Bangkok%202004/Capsules/1058.aspx

Next-Generation Fusion Inhibitors

Animal dataEnhanced pharmacokinetic propertiesPotential with once-weekly dosing

Delmedico M, et al. CROI 2006. Abstract 48.

In vitro dataHigh genetic barrier Active against ENF-resistant virus

Fold Decrease in Activity

Number of Mutations

Plasma Concentration (mm3/mL)

Time (Hours)

ENF

TRI-1144

TRI-999

Cynomolgus monkey IV, 1 mg/Kg

0

10

20

30

40

0

1

10

100

Clearance (mL/kg/hr) ENF 40 TRI-1144 11 TRI-999 7

(6)

(7)

(8)

(9)

> 4

3

2

1

TRI-999

ENF

TRI-1144

1000

100

10

0

(n)

For more information, see the Capsule Summary at http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202006/Capsules/48.aspx

RESIST: Phase 3 Study of TPV/r

1. Hicks C, et al. ICAAC 2004. Abstract 1137a. 2. Cahn P, et al. ICDT 2004. Abstract PL14.3.

APV, amprenavir/ritonavir; CPI, comparator protease inhibitor; IDV/r, indinavir/ritonavir; LPV/r, lopinavir/ritonavir; OBR, optimized background regimen; SQV/r, saquinavir/ritonavir; TPV/r, tipranavir/ritonavir; VL, viral load

The RESIST-1 trial (involving 630 patients in North and South America) and RESIST-2 trial (involving 876 Europeans and Australians) evaluated the use of OB therapy in combination with either tipranavir/ritonavir or a ritonavir-boosted comparator protease inhibitor (CPI/r) selected by the study site investigator in patients who were failing a PI-containing regimen and whose viral load was > 1000 copies/mL. Patients underwent baseline genotype resistance testing and were randomized to either the tipranavir arm (500 mg with 200 mg ritonavir twice daily) or a comparator PI arm, in which patients could receive ritonavir-boosted amprenavir, indinavir, lopinavir, or saquinavir twice daily (as selected by the investigator), plus an optimized background regimen.

Entry criteria required that the patient have at least 1 primary mutation at codon 30, 46, 48, 50, 82, 84, or 90, but no more than 2 mutations at codons 33, 82, 84, or 90the mutations believed at the time to be particularly associated with tipranavir resistance. In the RESIST-1 trial at baseline, patients had high viral loads (median, 4.8 log10 copies/mL) and relatively low CD4+ cell counts (median, 123 cell/mm3) and were highly resistant to current PIs with a median > 75-fold change in phenotypic susceptibility to lopinavir. Most patients (61%) in the comparator PI arm received lopinavir/ritonavir, while 21% received saquinavir/ritonavir and 14% received amprenavir/ritonavir. Enfuvirtide was included in 36% of the regimens (although all patients who received enfuvirtide were not necessarily naive to enfuvirtide at study entry) and enfuvirtide use was balanced between the arms by stratification. The median fold change in susceptibility to tipranavir at baseline was 1.9.

For more information, please go online to: http://www.clinicaloptions.com/hiv/conf/icaac2004/cs/1137a.asp

Twice as many TPV/r patients achieved VL

Viral load reductions from baseline at Week48 were significantly greater in TPV/r arm than control

Mean VL reduction (log10 copies/mL) p

Treatment response at Week 48 in ENF nave patients taking TPV/r + ENFITT NC=F

Tolrance dans Resist 1&2

RESIST Week 48 combined analysis

*

Safety - laboratory abnormalities (Grade 3/4 )

TPV/r has a similar profile to CPIs/r studied in RESIST, with two exceptions elevations in liver enzyme and lipid levels

TPV/r (n=738) (%)

CPI/r (n=732) (%)

ALT

9.7

4.2

AST

6.1

1.8

Bilirubin

0.7

0.5

White blood cell decrease

5.7

5.6

Amylase

6.0

7.0

Total cholesterol

2.1

0.4

Triglycerides

24.9

13.0

Week 48 laboratory abnormality data were available for 738 patients who took TPV/r and 732 patients who took CPI/r. Grade 3/4 laboratory abnormalities occurred at a similar frequency in both treatment groups, except for elevated liver enzyme and lipid levels. A higher proportion of patients taking TPV/r had Grade 3/4 AST, ALT, total cholesterol or triglyceride levels than control patients.

CAT en cas dintolrance hpatiqueHpatite clinique ou ASAT/ALAT > 10 x N: Arrt du Tipra

Si autre cause identifie: rintroduction possible aprs normalisation des testsSi pas dautre cause indentifie: pas de r-introduction

ASAT/ALAT < 10 x N: poursuite Tipra possible sisurveillance clinique et biologique rapproche



POWER 1 and 2: Week 48 Outcomes With DRV/RTV + OBR

Ongoing 96-week randomized trial in 3-class experienced patients 1 primary PI mutationVL > 1000 copies/mLDRV/RTV 600/100 mg BID chosen as optimal dose at Week 24Baseline VL: 4.4-4.7 log10 copies/mLBaseline CD4+ cell count:POWER-1: 99-113 cells/mmPOWER-2: 176-197 cells/mm

Lazzarin A, et al. IAC 2006. Abstract TUAB0104

DRV, darunavir; OBR, optimized background regimen; QD, once daily.For more information, go to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Toronto%202006/Capsules/TUAB0104.aspx?Track=Resistance



POWER 1 and 2: HIV RNA < 50 copies/ mL at Week 48 (ITT-TLOVR)

DRV/RTV 600/100 mg BID

*P < .001 vs comparator PI/RTV

Lazzarin A, et al. IAC 2006. Abstract TUAB0104

45%*

12%

46%*

10%

0

20

40

60

80

100

0

4

8

12

16

20

24

28

32

36

40

44

48

Weeks

1

2

Control

Pts With VL < 50 c/mL (%)

Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit

For more information, go to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Toronto%202006/Capsules/TUAB0104.aspx?Track=Resistance

Intrt dassocier deux molcules actives

24 %

55 %

20

40

60

80

100

< 400 copies/ml

Patients (%)

TORO S48

LPV/r

Enfuvirtide + LPV/r

20

40

60

80

100

37 %

67 %

NNRTI de seconde gnration: TMC 125 Etravirine

TMC125 in Treatment-Experienced Patients

Open, phase 2a study16 HIV-infected menFailing efavirenz or nevirapineResistance to efavirenzCD4+ cell count: 389 cells/mm3Viral load: 10,753 copies/mLTMC125 900 mg BID + continue NRTIs for 7 daysAfter 7 days, median 0.9-log decrease in viral load

Gazzard BG, et al. AIDS. 2003;17:F49-F54.

TMC125 is a potent NNRTI both in vitro and in vivo, and is one of the most promising second-generation NNRTIs. This NNRTI has strong in vitro activity against virus that is resistant to current NNRTIs, with an IC50 of < 10 nM against HIV-1 variants with the K103N, V106A, Y181C, or G190A/S mutations. A viral variant with 2 mutations (K103N and L100I) displayed a 19-fold decrease in susceptibility to TMC125 in vitro, although the IC50 remained < 20 nM.

The short-term activity of TMC125 has been clearly demonstrated in patients who have virus resistant to first-generation NNRTIs. In an open-label phase 2a study, subjects receiving a failing NNRTI-containing regimen replaced their NNRTI with TMC125 for 7 days, while the rest of the regimen was continued unchanged. All patients had > 35 fold decreased sensitivity to NVP. NNRTI mutations found included L100I, K103N, Y181C, Y188L, G190A/S, with 12 patients having multiple NNRTI mutations. All patients had NRTI mutations and all but one had protease mutations.

Despite the presence of a median 116-fold loss of susceptibility to efavirenz at baseline, these subjects experienced a median decline in plasma HIV-1 RNA level of 0.9 log10 copies/mL over 7 days. The fact that TMC125 was added to ongoing therapy may have blunted the maximum viral load change observed. 12 patients (75%) had a decrease in viral load of at least 0.5 log10; in 7 patients (44%) a decrease greater than 1 log10 was observed. 11 patients reported Grade 1 adverse events. Diarrhea (n = 5), and headache (n = 4) were most common.



TMC125-C223: Virologic Response to ETV at Week 48

N = 199 HIV-infected patients with NNRTI resistance and 3 primary PI mutationsMedian fold NNRTI baseline resistanceNVP: 61.3 EFV: 41.4ETV: 1.6Patients randomized to ETV (400 mg BID) + NRTIs LPV/RTV ENFETV (800 mg BID) + NRTIs LPV/RTV ENFActive control: best available regimen from licensed agents (NNRTIs excluded)

Pts With VL < 50 c/mL at Wk 48 (%)

0

5

10

15

20

25

0%

22%

CPI

23%

ETV 400 mg BID

Cohen C, et al. IAC 2006. Abstract TUPE0061.

ETV 800 mg BID

CPI, comparator protease inhibitor; ETV, etravirine.

Nouvelle classe dARV: Inhibiteurs de CCR5

Structure enveloppe du VIH et ciblespour linhibition de la fixation et de la fusionMcanisme daction du TNX-355Adapt de Moore J.P. et al., Proc Natl Acad Sci USA. 2003;100:10598-10602141

CCR5 Inhibitors in Development

1. Lalezari J, et al. ICAAC 2004. Abstract H-1137b.2. Schurmann D, et al. CROI 2004. Abstract 140LB. 3. Pozniak AL, et al. ICAAC 2003. Abstract H-443.

Aplaviroc (GW873140), a CCR5 inhibitor in clinical development, has a shorter half-life than other CCR5 inhibitors such as maraviroc, but has a prolonged receptor occupancy that may lead to a longer activity half-life in vivo. In a phase 2a dose-ranging monotherapy trial, HIV-infected patients with R5 virus were given aplaviroc doses ranging from 200 mg once daily to 600 mg twice daily. The investigators found a dose-response relationship, with patients in the highest dose arm achieving a 1.6 log10 copies/mL reduction after 10 to 12 days of treatment with aplaviroc. Despite the fact that aplaviroc was discontinued after 10 days, there was further virologic reduction several days after discontinuation in most of the dose arms. The drug was generally well tolerated, with the most common adverse events being minor GI side effects that resolved after the first few days of therapy. Longer-term dose-ranging studies of this agent in both treatment-naive and treatment-experienced patients have started. For more information, please go online to: http://clinicaloptions.com/hiv/conf/icaac2004/cs/1137b.asp

Maraviroc (formerly known as UK-427,857) is also a reversible inhibitor of CCR5 that does not stimulate this coreceptor and is orally bioavailable with potent in vitro activity (IC90 ~ 2 nM). The first study in HIV-infected volunteers examined once-daily doses of maraviroc 25 and 100 mg vs placebo over a 10-day period in CCR5-tropic HIV-infected volunteers who were not on treatment. The average peak reduction in viral load in the higher dose arm was approximately 1.4 log10 copies/mL. Subsequent data on this CCR5 inhibitor showed a relationship between the area under the plasma concentration-time curve (AUC) and the extent of antiviral activity Not surprisingly, the antiviral activity of maraviroc was related to the extent to which CCR5 coreceptors were occupied by this molecule. Maraviroc may be a substrate for PgP, which would suggest that there will be an interaction with some PIs, in particular ritonavir and tipranavir. In vivo concentrations of this drug are decreased by efavirenz and increased by about 2-fold when coadministered with lopinavir/ritonavir. Phase 2b studies of this agent are well underway and phase 3 studies in both treatment-naive and treatment-experienced patients are expected to commence shortly. For more information, please go online to: http://clinicaloptions.com/hiv/conf/iac2004/cs/4489.asp

Vicriviroc (SCH D) is potent against most R5 viruses in vitro with an IC50 in the range of 20 nM. This agent does not bind to human ether--go-gorelated gene (hERG) channels in vitro, a finding that suggests that it would not prolong QTc intervals in humans. (An earlier compound, SCH C, was the first CCR5 antagonist to show activity in HIV-infected individuals, but this compound, at higher doses, prolonged the QTc interval and development was halted.) In an initial study, HIV-infected individuals who were not on antiretroviral therapy and who were documented to have R5 virus at baseline were given 1 of 3 doses of vicriviroc (10, 25, or 50 mg twice daily) or placebo for 14 days. The highest dose reduced HIV-1 RNA levels by an average of 1.6 log10 copies/mL at Day 15, and the activity appeared to persist for several days after the drug was discontinued. In general, the agent was well tolerated and no prolongation of the QTc interval was observed. The concentrations of this agent are increased by ritonavir, and once-daily dosing with ritonavir, or in ritonavir-containing regimens, is being studied. Currently a phase 2b study of 3 doses of vicriviroc in treatment-experienced patients with R5 virus who receive this compound plus optimized therapy is ongoing and phase 3 studies are being planned. For more information, please go online to: http://clinicaloptions.com/hiv/conf/croi2004/cs/140lb.asp

Maraviroc : rsultats 24 semaines dun essai chez des patients prtraits,infects par une souche duale/mixte X4/R5 (1)Essai de phase IIb (Pfizer A400 1029) randomis, en double aveugle contre placeboSlection et randomisation

Traitement optimis + MARAVIROC (150 mg bid)Traitement optimis + MARAVIROC (150 mg qd)Traitement optimis + PlaceboCritre principal defficacitJ04-6 semainesS2448 semainesCritres de slection : souche duale/mixte X4/R5, ou X4 ou tropisme phnotypique indterminpatients pr-traits et/ou avec rsistances multiples au moins 1 ARV actif dans traitement optimis (3 6 ARV)Mayer H., IAC 2006, Abs. THLB0215136

Maraviroc : rsultats 24 semaines dun essai chez des patients prtraits,infects par une souche duale/mixte X4/R5 (2)Efficacit 24 semaines pour les 167 patients valus avec souche initiale duale/mixte parmi 190 patients randomiss dont 186 traits : exclusion de lanalyse de 19 patients (X4, n = 8 ; R5, n = 1 ; tropisme indtermin, n = 10)Mayer H., IAC 2006, Abs. THLB0215137

Rsultats S24Placebo + TOn = 58MVC qd + TO n = 57MVC bid + TO n = 52Diminution moyenne de CV (log10c/ml)-0,97-0,91-1,20Diffrence de rduction de CV entre les bras (log10c/ml) (IC 97,5 %)+0,06 (-0,53 ; +0,64)-0,23 (-0,83 ; +0,36)CV < 400 c/ml CV < 50 c/ml24,1 %15,5 %24,6 %21,1 %30,8 %26,9 %Diminution moyenne CV (log10c/ml)chez les patients recevant enfuvirtide-0,89 -1,26-1,44Evolution des CD4 (/mm3)+36+60+62Evolution des CD4 (/mm3) si tropisme X4 lors de lchec virologique-104(n = 2)+48(n = 12)+33(n = 12)

Vicriviroc : Essai de phase IIb (ACTGA5211) (1)118 patients prtraits, CV 5 000 c/ml, Tropisme R5Gnotype et phnotype de rsistance pour slectionner le traitement optimisJ0J14S24S48Poursuite traitement ARV en coursRandomisation(stratification surutilisation ENF etCD4 < ou 50/mm3)+ Placebo + Vicriviroc 5 mg qd+ Vicriviroc 10 mg qd+ Vicriviroc 15 mg qdTraitement ARV optimis (TO)Objectif primaire : activit antivirale du Vicriviroc (VCV) J14 (puissance suffisante pour dtecter une diffrence de rduction de CV 0,7 log10 c/ml J14)Gulick R., IAC 2006, Abs. THLB0217138

Diminution moyenne ARN VIH (log10 c/ml) S24 (ITT)Vicriviroc : Essai de phase IIb (ACTGA5211) (2)% CV < 400 c/ml et < 50 c/ml S24Placebo11 %7 %

VCV 5 mg43 %26 %VCV 10 mg53 %40 %VCV 15 mg47 %27 %Gulick R., IAC 2006, Abs. THLB0217139

Vicriviroc : Essai de phase IIb (ACTGA5211) (3)TropismeAu screening : Tropisme R5 exclusif = 118 (100 %)A J0 : Tropisme R5 exclusif = 102 (86 %), Mixte/Duale = 12 (10 %) , Non disponible = 4Sous traitement, changement de tropisme chez 13/106 patients : 1 placebo, 7 VCV 5 mg, 3 VCV 10 mg, 2 VCV 15 mgRponse virologique (ARN VIH log10 c/ml) S24 ; VCV 10 + VCV 15Tropisme R5 J0 (n = 71) - 1,83 Tropisme mixte/dual J0 (n = 10)- 0,77 p = 0,01

Effets indsirables : pas de diffrence dans la frquence des EI de grade 3 et 4 entre les groupes, aucun cas de convulsions

Survenue de cancersGroupes VCV : 5/83 [maladie de Hodgkin (n = 2), lymphome (n = 2), cancer gastrique (n = 1)]Groupe placebo : 2/28 dont 1/2 ayant t switch pour VCV 10 mg pendant 3 mois, avec survenue du cancer 1 mois aprs larrt du VCVGulick R., IAC 2006, Abs. THLB0217140

Nouvelle classe dARV: Inhibiteur dattachement

TNX-355 : essai de phase II (1)82 patients prtraits par les 3 classes, ARN VIH 10 000 c/ml, CD4 50/mm3, Slection TO sur test rsistanceEtude randomise en double aveugleSwitch pour TNX-355 + nouveau TO en ouvert possible si chec virologique (diminution CV < 0,5 log10 c/ml depuis J0)TNX-355 15 mg/kg* + TOn = 27TNX-355 10 mg/kg** + TOn = 28Placebo + TOn = 27* 1 perfusion toutes les 2 semaines ** 1 perfusion/semaine pendant 8 semaines puis toutes les 2 semaines Si chec virologiqueTNX-355 15 mg/kg* + nouveau TOTNX-355 15 mg/kg* + nouveau TOTNX-355 15 mg/kg* + nouveau TORandomisationNorris D., IAC 2006, Abs. THLB0218142

TNX-355 : essai de phase II (2)Dlai perte rponse virologique = 253 j pour TNX-355 15 mg/kg versus 230 j pour TNX-355 10 mg/kg versus 0 j pour placebo Tolrance clinique et biologique non diffrente entre TNX-355 et placebo, pas dEIG, pas de raction au site de perfusionCritre principal = rduction CV S24 (analyse en LOCF)Norris D., IAC 2006, Abs. THLB0218143

Nouvelle classe dARV: Inhibiteurs dIntgrase

Inhibiteur dintgrase MK-0518en traitement initial : essai de phase IIb chez NAIFSEssai international (hors Europe), phase IIb, randomisPatients nafs dARV (CV > 5 000 c/ml, CD4 > 100/mm3)Comparaison de 5 bras (8 patients par bras de MK-0518 ayant reu 10 jours de monothrapie pralable par MK-0518)Markowitz M., IAC 2006, Abs. THLB0214

Inhibiteur dintgrase MK-0518en traitement initial : essai de phase IIb chez NAIFSSemainesPatients avec CV < 50 c/ml (%)* Diffrence significative (p < 0,001) S4 et S8 entre chaque dose de MK-0518 et le bras EFV% CV < 50 c/mlMK-0518 100 mg bidMK-0518 200 mg bidMK-0518 400 mg bidMK-0518 600 mg bidEFVMarkowitz M., IAC 2006, Abs. THLB0214

Inhibiteur dintgrase MK-0518en traitement initial : essai de phase IIb chez NAIFSTolrance satisfaisante :effets indsirables modrs et pas plus frquents quavec EFVun seul arrt pour augmentation ASAT/ALATMarkowitz M., IAC 2006, Abs. THLB0214

Integrase Inhibitor: GS-9137

10-day monotherapy studyN = 40, HIV positive, HCV/HBV negativeARV naive or experienced off treatmentRandomized 1:1 vs placeboDosing 200 mg BID400 mg BID 800 mg QD800 mg BID 50 mg/RTV 100 mg QDPK studies Days 1 and 10 Trough sampling through Day 21

No serious adverse eventsOnce-daily dosing with RTV to be investigated in phase II trial with experienced patients

DeJesus E, et al. CROI 2006. Abstract 160LB.

BL

1

2

3

4

7

10

11

14

21

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

200 BID

400 BID

800 BID

50 + RTV QD

Placebo

800 QD

Day

Log10 Change HIV-1 RNA

Dosing

Nouvelle classe dARV: Inhibiteurs de la maturation

Novel Maturation Inhibitor, PA-457Orally bioavailable; 70-hour half-life in HIV-infected patientsTreatment response correlated with plasma exposure and trough concentrationLinear pharmacokinetics with multiple dosing; low interpatient variabilityMaximum response not seen yet with doses studiedIn vitro resistance studies confirm mode of actionNo resistance seen to date in short-term clinical studiesSmith P, et al. CROI 2006. Abstract 52.

Antiviral Activity of PA-457, First Maturation Inhibitor

PA-457 blocks cleavage of capsid precursor CA-SP1 to mature p24Does not inhibit HIV proteaseRandomized, double-blind, placebo-controlled, single-dose study6 HIV+ pts per dose arm (placebo vs PA-457 75, 150, or 250 mg)CD4+ cell count 200 cells/mm3, VL 5000-250,000 copies/mL8/12 pts in 150 and 250 mg arms had > 0.3 log10 VL reductionActivity observed in 2 patients with NRTI+NNRTI or NNRTI+PI resistance mutationsAll doses well-toleratedEfficacy studies planned for later in 2005

Martin D, et al. CROI 2005. Abstract 159.

Conclusion (1): nouveaux ARV en dveloppement actif

Inhibiteur de la maturation

PA 457

Inhibiteur dIntgrase

MK-0518

GS-9137

Inhibiteurs dentre

Inhibiteurs deCXCR4 AMD070 KRH 3955KRH 3140Inhibiteurs de CCR5 MaravirocVicrivirocInhibiteurs de FusionTRI-1144TRI-999Inhibiteur de lattachementPRO 140TNX 355

Conclusion (2)Diagnostiquer tt les chappements/checs virologiques

Diagnostiquer les dterminants individuels de lchec

Tirer profit du dveloppement dynamique des nouveaux antirtroviraux: essais thrapeutiques, accs prcoces pr-AMM

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Mean VL reductions at Week 48 were -1.14 log10 copies/mL in TPV/r arm and -0.54 log10 copies/mL in CPI/r arm. P

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