Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings

Post-Congress Activity Expert Review on the EACS, HIV & Aging

and the AASLD Meetings

With Dr. Mark Wainberg (moderator) and Dr. Fred Crouzat, Dr. Alice Tseng, and

Dr. Stephen Shafran

The 13th European AIDS Conference (EACS) MeetingOctober 12-15, 2011Belgrade, Serbia

Overview

•STARTMRK 192•VIKING 24•ATL to CPL•TDR in MSM

Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve

HIV-1-Infected Patients:Week-192 Subgroup Analyses

from STARTMRKJ. K. Rockstroh, A. Lazzarin, J. Zhao,

A. Rodgers, M. J. DiNubile, B-Y. Nguyen, R. Leavitt, H. Teppler, and P. Sklar

for the STARTMRK Study Team

EACS UPDATE

STARTMRK 192BACKGROUNDBACKGROUND•At 192 weeks, RAL was non-inferior compared to EFV•With non-completer-as-failure (NC = F), VL < 50 at 192 = 76% vs. 67% •95% CI of 9% [2, 16] favouring RAL•Presented at EACS: week 192 secondary observed-failure (OF) analyses

METHODSMETHODS•ARV naïve, blinded and randomized to RAL(BID) + TVD or EFV(QHS) + TVD•Viral susceptibility to EFV, FTC, & TDF, VL > 5000, any CD4•Planned 240 week

RESULTSRESULTS•Wk 192 OF analyses 235/281 (84%) RAL vs. 222/282 (79%) in EFV group were included…

CONCLUSIONSCONCLUSIONS•Both treatment groups showed generally consistent virologic and immunologic outcomes at Wk 192, including high viral loads

Rockstroh JK, et al. Long-term Efficacy of Raltegravir or Efavirenz Combined with TDF/FTC in Treatment-Naïve HIV-1-Infected Patients: Week-192 Subgroup Analyses from STARTMRK . [Poster PS1/1] Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Proportion of Patients with <50 vRNA c/mL at Wk 192by Demographic Factors (OF Approach)

RaceWhiteBlackAsianHispanicMultiracial

Total 214/235 (91) 189/222 (85)

EFV Groupn/N (%)

Difference in Response Rates % (95% CI)

RAL Groupn/N (%)

Age (years)Median>Median

109/122 (89)105/113 (93)

105/129 (81)84/93 (90)

GenderMaleFemale

173/191 (91)41/44 (93)

157/185 (85)32/37 (86)

Viral SubtypeClade BNon-Clade B

164/181 (91)47/51 (92)

149/177 (84)35/40 (88)

86/93 (92)21/24 (88)31/34 (91)47/53 (89)28/30 (93)

75/83 (90)17/22 (77)25/28 (89)44/57 (77)28/32 (88)

-50 -25 0 25 50

Favors EFV Favors RAL


Proportion of Patients with <50 vRNA c/mL at Wk 192by Baseline Prognostic Factors (OF Approach)

Total 214/235 (91) 189/222 (85)

Difference in Response Rates % (95% CI)

EFV Group n/N (%)

RAL Group n/N (%)

Baseline Plasma HIV RNA (c/mL)100,000>100,000

98/105 (93)116/130 (89)

86/106 (81)103/116 (89)

Baseline CD4 Counts (cells/mm3)50>50 and 200>200

17/22 (77)84/88 (95)

113/125 (90)

25/29 (86)71/85 (84)

93/108 (86)

Hepatitis StatusHepatitis B or C PositiveBoth Hepatitis B and C Negative

11/12 (92)203/223 (91)

12/13 (92)177/209 (85)

-50 -25 0 25 50Favors EFV Favors RAL


% Responders

with vRNA <50 c/mL

(n/N)

Change from BL CD4 Count (cells/mm3)

NC = F OF OF

RAL76.2

(214/281)91.1

(214/235)361

EFV67.0

(189/282)85.1

(189/222)301

Δ RAL - EFV9.0*

(1.6, 16.4)6.0*

(0.1, 12.2)60

(24, 95)

*p-value for non-inferiority <0.001

Summary of Efficacy at Week 192


MLMC Clinical Trends: Sept 2011

MLMC Database: September 2011Utilization of EFV+TVD and RAL+TVD, most recent CD4 and VL

Viral Load (copies/mL) CD4 Count (cells/µL)Regimen # of

Patients<50 <50 On

Rx>90 Days

50-400

400-10,000

>10,000 <200 200-350

350-500

>500

FTC + TDF + EFV 493 91.7% 96.1% 3.7% 2.0% 2.6% 2.6% 10.9% 30.9% 55.6%

FTC + TDF +RAL 76 95.8% 97.1% 1.4% 0% 2.8% 6.9% 4.2% 22.2% 66.7%


MLMC Clinical Trends: Sept 2011


STARTMRK 192BACKGROUNDBACKGROUND•At 192 weeks, RAL was non-inferior compared to EFV•With non-completer-as-failure (NC = F), VL < 50 at 192 = 76% vs. 67% •95% CI of 9% [2, 16] favouring RAL•Presented at EACS: week 192 secondary observed-failure (OF) analyses

METHODSMETHODS•ARV naïve, blinded and randomized to RAL(BID) + TVD or EFV(QHS) + TVD•Viral susceptibility to EFV, FTC, & TDF, VL > 5000, any CD4•planned 240 week

RESULTSRESULTS•Wk192 OF analyses 235/281 (84%) RAL vs. 222/282 (79%) in EFV group were included…

CONCLUSIONSCONCLUSIONS•Both treatment groups showed generally consistent virologic and immunologic outcomes at Wk 192, including high viral loads


Dolutegravir (DTG, S/GSK1349572) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral

Suppression at Week 24 in the VIKING Study

V Soriano, J Cox, JJ Eron, et al.

EACS UPDATE

VIKING 24OBJECTIVESOBJECTIVES•Assess Dolutegravir (DTG) in patients with Raltegravir (RAL) resistance

METHODSMETHODS•2 sequential cohorts with resistance to RAL and ≥2 other ARV classes•Received DTG 50mg QD (Cohort 1) or 50mg BID (Cohort 2)•Continued with failing background to day 11, then optimized•Needed at least 1 fully active ARV in OBR

RESULTSRESULTS•Baseline and antiviral responses at day 11 and Week 24: (see table)•Self limited grade 1-2 diarrhea most common AE in 3 & 7 subjects in Cohorts I & II respectively

CONCLUSIONSCONCLUSIONS•DTG exerts potent antiviral activity in highly treatment experienced RAL resistant patients•Confirms DTG 50mg BID for phase III trial in subjects with RAL or EVG (ongoing)

Soriano V, et al. Dolutegravir (DTG, S/GSK1349572) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the VIKING Study. [Poster PS1/2]. Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Key Baseline Characteristics Cohort I (n=27)DTG QD

Cohort II (n=24)DTG BID

Median CD4+ cells/mm3 114 202

Median HIV-1 RNA log10c/mL 4.5 4.3

Q148 + ≥ 1 9 (33%) 11 (46%)

N155 or Y143 or other 18 (67%) 13 (54%)

Median RAL FC (range) > 161(0.67 - >max

> 128(0.78 - >max)

Median years prior ARV 14 15

PSS of OBR =0/1/≥2 12/7/8 1/9/14

VIKING 24Baseline Responses at Day 11


Antiviral Response to DTG Cohort I (n=27)DTG QD

Cohort II (n=24)DTG BID

Plasma HIV-1 RNA log10c/mL reduction at Day 11*

-1.45 (S.D. = -0.77) -1.76 (S.D. = 0.54)

% < 50 c/mL (TLOVR) at Wk 24 11/27 (41%) 18/24 (75%)

% < 400 c/mL (TLOVR) at Wk 24 14/27 (52%) 20/24 (83%)

% < 2 c/mL (TLOVR) at Wk 24 3/27 (11%) 9/24 (38%)

*p = 0.017 for treatment difference was derived using multivariate linear regression model (F-test) by adjusting for baseline viral load, DTG, FC, IN genotypic pathway, PSS of failing background regimen.

VIKING 24 Antiviral Response at Week 24


MLMC Clinical Trends: Sept 2011 “Other Classes”

Maraviroc Enfuvirtide Raltegravir Study/Placebo


EACS UPDATEATL to CPL

Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet

Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in

Virologically Suppressed, HIV-1 Infected Subjects

Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet

Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in

Virologically Suppressed, HIV-1 Infected Subjects

C Cohen, A Mills, E DeJesus, B Rashbaum, C Brinson, K Yale, S Ramanathan, H Wang, A

Jandourek, and A Cheng.

ATL to CPLBACKGROUNDBACKGROUND•A previous PK study in healthy volunteers showed switching from Efavirenz (EFV) to Rilpivirine (RLP) reduced RPV Cmin up to 25% for 4 weeks•Clinical implications evaluated here, switching suppressed HIV-1 infected patients from EFV to RPV

METHODSMETHODS•Open labelled, EFV/TDF/FTC STR > 3 months, change due to intolerance•Evaluate efficacy at 12 weeks, planned 48 weeks•PK assessed weeks 1, 2, 4, 6, 8 & 12 along with safety and tolerability

RESULTSRESULTS•100% maintain <50 at 12 weeks, no A/E’s discontinuations•RPV Ctrough at “therapeutic levels” at 2 week post-switch

CONCLUSIONSCONCLUSIONS•Brief EFV inductive effects on RPV metabolism may not be clinically relevant in suppressed patients

Cohen C, et al. Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet Regimen (STR) toEmtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

Study Schema and Endpoints

FTC/RPV/TDFSTR

Primary endpoint: % of subjects with HIV-1 RNA <50 c/mL at Week 12 post-switch - ITT population FDA Snapshot Analysis

Secondary endpoints: Safety of FTC/RPV/TDF over 24 & 48 wksHIV-1 RNA <50 c/mL at Week 24 and Week 48

Pharmacokinetics of RPV after switchingITT = intent to treat

12 Wks 48 Wks

•n=50•Stable on EFV/FTC/TDF for ≥ 3 months•VL <50 c/mL ≥ 8 wks•No genotypic resistance•eGFR > 50 mL/min

24 Wks


Primary Endpoint: HIV-1 RNA <50 copies/mL at Week 12 (FDA Snapshot Analysis – ITT Population)

.

0%

20%

40%

60%

80%

100%

FTC/RPV/TDF

%

HIV

-1 R

NA

< 5

0c/m

L

49/49

100%

95% CI (92.7, 100.0) calculated using the 2-sided exact method


Secondary Endpoint: RPV PK after Switching from EFV

• EFV mean Ctrough above IC90 (~10 ng/ml*) up to ~4 weeks

• No subject had RPV below quantifiable levels at any visit

• RPV mean Ctrough within historic range by 2 weeks

*protein-binding adjusted; Corbett JW, et al. J Med. Chem 2000:43;2019-2030*protein-binding adjusted; Corbett JW, et al. J Med. Chem 2000:43;2019-2030

WeekRPV Ctrough

Mean (%CV), ng/ml

2 52 (47)

4-12 66 (51) - 84 (76)


ATL to CPLBACKGROUNDBACKGROUND•A previous PK study in healthy volunteers showed switching from Efavirenz (EFV) to Rilpivirine (RLP) reduced RPV Cmin up to 25% for 4 weeks•Clinical implications evaluated here, switching suppressed HIV-1 infected patients from EFV to RPV

METHODSMETHODS•Open labelled, EFV/TDF/FTC STR >3 months, change due to intolerance•Evaluate efficacy at 12 weeks, planned 48 weeks•PK assessed weeks 1, 2, 4, 6, 8 & 12 along with safety and tolerability

RESULTSRESULTS•100% maintain <50 at 12 weeks, no A/E’s discontinuations•RPV Ctrough at “therapeutic levels” at 2 week post-switch

CONCLUSIONSCONCLUSIONS•brief EFV inductive effects on RPV metabolism may not be clinically relevant in suppressed patients


Transmission of HIV Resistantto Non-nucleoside RT Inhibitors

in MSM in Europe

D. Frentz, D.A.M.C. van de Vijver, A. Abecasis, J. Albert, L. Bruun Jorgensen, O. Hamouda, C. Kuecherer, J.-C. Schmit, D. Struck, A.- M. Vandamme, J. Vercauteren, B. Asjo, C. Balotta, D. Beshkov, R. Camacho, A. Griskevicius, Z. Grossman, A. Horban, T.

Kolupajeva, K. Korn, L. Kostrikis, K. Liitsola, M. Linka1, D. Otelea, D. Paraskevis, R. Paredes, M. Poljak, E. Puchhammer-Stockl, R. Schuurman2, A. Sonnerborg, D.

Stanekova, M. Stanojevic, S. Zidovec Lepej, A.M.J. Wensing, C.Boucher, on behalf of the SPREAD-Programme

EACS UPDATETDR in MSM

TDR in MSM

BACKGROUND•Prospective monitoring of Transmission of Drug Resistance HIV (TDR)•26 European countries

METHODS•4317 patients newly diagnosed 2002-2007•Risk group and geographical stratification

RESULTS•48% MSM (n = 2072), 56% Western European origin

• NRTI BL Resistance stable from 2002 to 2007• PI BL Resistance decreased from 2002 to 2007• NNRTI BL Resistance increased from 2003 to 2007

Frentz D, et al. Transmission of HIV Resistant to Non-nucleoside RT Inhibitors Is Rising in MSM in Europe.Presented at the 13th European AIDS Conference (EACS), October 12-15, 2011, Belgrade, Serbia.

TDR in MSMRESULTS•Clades: B (63%), A (11%) and C (7%)•Overall prevalence of TDR was 8.8% in 2003 and 9.5% in 2007•By risk factors:

• MSM: 11.1%• Heterosexuals: 6.6% • IDU: 5.1%

•Transmitted NRTI resistance remained constant at 5%.•A decline in PI resistance was observed

• 3.9% in 2002 to 1.6% in 2007 (p=0.001)•Resistance to NNRTIs doubled

• 2.0% in 2002 to 4.1% in 2007 (p=0.004) • 58% carrying a K103N amino acid substitution

•The significant increase in resistance to NNRTIs and decrease in resistance to PIs were only observed in MSM (p=0.03 and p=0.005, respectively), but not in the heterosexual patients (p=0.68 and p=0.14, respectively).


Clinical Trends: Sept 2011 - BL GenotypesMLMC vs. European Trends

Group

European Cohort MLMC CohortAll Baseline Genotypes

Stanford Scores

2002 2007 >30 >60

Overall 8.8% 9.5% 10.8% 7.4%

MSM 11.1% 10.2% 6.4%

Heterosexual 6.6% 9.2% 6.1%

IDU 5.1% 4.0% 4.0%

NNRTI Resistance 2.0% 4.1% 4.9% 4.8%

PI Resistance 3.9% 1.6% 3.0% 2.4%

NRTI Resistance ~5.0% ~5.0% 7.0% 3.0%


TDR in MSM

BACKGROUND•Prospective monitoring of transmission of drug resistance HIV (TDR)•26 European countries

METHODS•4317 patients newly diagnosed 2002-2007•Risk group and geographical stratification

RESULTS•48% MSM, 56% Western European origin

• NRTI BL Resistance stable from 2002 to 2007• PI BL Resistance decreased from 2002 to 2003• NNRTI BL Resistance increased from 2003 to 2007

CONCLUSIONS•Sharp increase in transmitted NNRTI resistance in MSM in Europe requires further action given NNRTIs are commonly used in 1st line therapy


Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings

Documents