1 © 2009 merck & co., inc., whitehouse station, nj usa. all rights reserved, emerging patterns...

1© 2009 Merck & Co., Inc., Whitehouse Station, NJ USA. All rights reserved,

Emerging Patterns of Resistance to Integrase Inhibitors

Michael D. Miller, Robert M. Danovich, Marc Witmer, Bach-Yen Nguyen, Hedy Teppler, Jing Zhao, Richard J.O. Barnard , and Daria

Hazuda for the HIV-1 Integrase Inhibitor Development Teams, Protocol 004 Study Team, and BENCHMRK-1 and -2 Teams.

Merck and Co., Inc., West Point, PA


Raltegravir Resistance: Major pathways and longitudinal analysis

Resistance data from 5 clinical studies are generally consistent: – 3 studies in treatment-experienced patients( Protocols 005, 018, and 019)– 2 studies in treatment-naïve patients (Protocols 004 and 021)

Three pathways defined by primary mutations Y143C/H/R, Q148H/K/R, and N155H

Secondary mutations lead to higher resistance– If not present at VF, evolves at later time

Q148 pathway is preferred– Virus population can switch N155 to Q148 – When combined with secondary mutations, Q148 mutants lead to greater resistance


Impact of polymorphisms and minority variants?

Are baseline integrase polymorphisms associated with treatment success or failure? – Data from Protocol 018 (BENCHMRK 1)

Can minority RAL RAMs be detected at baseline, and are they associated with treatment success or failure?– Protocol 019 (BENCHMRK 2): patients with GSS = 0 – Protocol 004: patients who received RAL monotherapy followed by

combination therapy


Are baseline integrase polymorphisms associated with treatment success or

failure?

Data from Protocol 018 (BENCHMRK-1)


AcknowledgmentsAll patients who participated in BENCHMRK-1.

BENCHMRK-1 Investigators: Australia: Allworth A, Anderson J, Bloch M, Cooper DA, Hoy J, Workman C; Belgium: Clumeck N, Colebunders R, Moutschen M; Denmark: Gerstoft J, Larsen C, Mathiesen L, Pedersen C; France: Delfraissy JF, Dellamonica P, Katlama C, Molina JM, Raffi F, Reynes J, Vittecoq D, Yeni P; Germany: Arasteh K, Fatkenheuer G, Jaeger H, Rockstroh J, Stoehr A; Italy: Aiuti F, Carosi G, Cauda R, Chiodo F, Di Perri G, Filice G, Galli M, Lazzarin A,Vullo V; Peru: Castaneda M, Florez A, Mendo F, Paredes A, Salazar R, Ticona E; Portugal: Antunes R, Diniz A, Mansinho K, Saraiva da Cunha J, Sarmento R, Teofilo E, Vera J; Spain: Arrizabalaga J, Clotet Sala B, Domingo Pedrol P, Gatell Artigas J, Moreno Guillen S, Soriano Vazquez V; Switzerland: Hirschel B, Opravil M; Taiwan: Lin H-H, Sheng W-H, Wang J-H; Thailand: Sungkanuparph S, Suwanagool S.

Merck Research Laboratories: M. Nessly, J. Chen, A. Rodgers, J. Zhao, X. Xu, D. Hazuda, R. Isaacs, M. Miller, R. Danovich, R. Rhodes, B. Jackson, K. Strohmaier, P. Sklar, R. Leavitt, H. Teppler, B-Y. Nguyen.

Siemens Health Solutions: SD Pandit, H Kapur, D Sebisanovic, AJ Uzgiris


Like all HIV-1 proteins, integrase is polymorphic

http://www.retrovirology.com/content/5/1/74/figure/F1


Integrase polymorphisms do not significantly affect InSTI antiviral activity in vitro

Polymorphisms do not seem to affect RAL or EVG sensitivity in vitro, BUT

No data available regarding possible effect of baseline polymorphisms on RAL treatment outcome

Fold

-Cha

nge

IC50

0.0

0.5

1.0

1.5

2.0

2.5

3.0

All Isolates(N = 144)

Non-B Subtype Isolates(N = 23)

Data from Monogram Biosciences PhenoSense assay


Do IN polymorphisms affect RAL treatment outcome?

Determine baseline sequences for patients enrolled in BENCHMRK-1 who received RAL + Optimized Background Therapy– 51 patients who experienced virologic failure by week 48 (35 with RAL

resistance)– 138 patients who did not experience virologic failure by week 48 (partial data

set)

Determine the frequency of specific IN polymorphisms found in baseline sequences from both populations:– Known RAL resistance mutations (e.g., the secondary mutation T97A)– Polymorphisms found at a frequency of >10%– NOT AN EXHAUSTIVE LIST


Analysis of Baseline RAMs and Treatment Outcome in BENCHMRK-1

Conclusions: – No primary RAMs detected at Baseline – One secondary RAM detected, at baseline, no

correlation with virologic success/failure

Y143C/H/R

N155H

Q148H/K/R

L74M

E92Q

T97A

E138A/K

G140A/S

Not detected

Not detected

Not detected

Not detected

Not detected

2%

Not detected

Not detected

Not detected

Not detected

Not detected

Not detected

Not detected

2%

Not detected

Not detected

Treatment Successes2

Treatment Failures3

Statistical Significance4

N/A

N/A

N/A

N/A

N/A

p = 1

N/A

N/A

Mutation1

1 Mutations in bold yellow are primary RAL RAMs, others are secondary2 Partial data: N = 1383 Includes patients with and without RAL resistance at VF

4 Fisher’s exact test 2-sided; N/A, not applicable

% of Baseline Sequences with specific mutation


All polymorphisms analyzed to date (I)

E11D

K14R

S17N

R20K

V31I

S39C

M50I

I72V

T97A

L101I

T112I

T112V

I113V

S119G

S119P,G,R,T,A

22%

17%

38%

17%

33%

10%

6%

36%

2%

62%

20%

14%

11%

4%

29%

33%

18%

16%

18%

33%

22%

20%

29%

2%

69%

10%

12%

10%

4%1

20%

p = 0.136

p = 1

p = 0.003

p = 1

p = 1

p = 0.052

p = 0.009

p = 0.49

p = 1

p = 0.496

p = 0. 13

p = 0.813

p = 1

p = 1

p = 0.235


Treatment Failures2

Statistical Significance3Polymorphism


1Partial data: N = 1382Includes patients with and without RAL resistance at VF

3 Fisher’s exact test 2-sided


All polymorphisms analyzed to date (II)

T122I

T124A

T124N

T124N/S/G/A

T125A

M154I

K160Q

V201I

T206S

S230N

L234I

D256E

S283G

12%

38%

11%

55%

40%

6%

4%

54%

18%

12%

14%

26%

20%

10%

27%

10%

41%

43%

8%

4%

57%

29%

16%

16%

12%

14%

p = 0.80

p = 0.11

p = 0.602

p = 0.118

p = 0.74

p = 0.737

p = 1

p = 0.536

p = 0.109

p = 0.42

p = 0.816

p = 0.048

p = 0.401


Treatment Failures2

Statistical Significance3Polymorphism


1Partial data: N = 1382Includes patients with and without RAL resistance at VF

3 Fisher’s exact test 2-sided


Conclusions from analysis of baseline polymorphisms and virologic outcome

RAL resistance-associated mutations (RAMs): – No primary RAL RAMs (i.e., 143, 148, 155) detected at baseline– Secondary RAL RAMs: Only T97A observed at baseline; frequency not

significantly different between patients with and without virologic failure

25 of 28 baseline polymorphisms analyzed to date had no significant difference in frequency between virologic failures and treatment successes– Frequency of S17N, M50I, and D256E were statistically different between

treatment successes and virologic failures– these need to be characterized further

– Additional analyses needed on polymorphism frequency by subtype, association with RAL resistance pathways

Caveat to all analyses: numbers of patients tested are relatively small


Can minority RAL resistance variants be detected at baseline, and are they associated with treatment success or

failure?

Data from patients in Protocol 019 (BENCHMRK-2) with GSS = 0

See Poster #685, (Liu et al.)


AcknowledgmentsAll patients who participated in BENCHMRK-2.

BENCHMRK-2 Investigators: Brazil: Grinsztejn, B., Madruga, JV., Schechter, M. Canada: Baril, J-G., Loutfy, MR., Montaner, JS., Tremblay, C., Tsoukas, CM., Vezina, S. Colombia: Cortes, JA., Mendoza, H., Velez, J. Mexico: Quintero Perez, N., Ramos, J., Rodriguez, E. Puerto Rico: Morales-Ramirez, JO., Sepulveda, GE. US: Aberg, J., Beatty, GW., Benson, P., Bolon, RK., Bredeek, UF., Bruno, C., Campbell, T., Campo, R., Coodley, GO., Corales, RB., DeJesus, E., Eron, JJ., Fessel, WJ., Fetchick, RJ., Gonzales, CJ., Hicks, C., Horberg, MA., Klein, DB., Kozal, MJ., Kumar, PN., LaMarca, A., Lennox, JL., Lichtenstein, KA., Liporace, R., Little, SJ., Luetkemeyer, A., Mariuz, P., Markowitz, M., McMahon, DK., Perez, G., Pierone, G., Reichman, RC., Rhame, F., Shalit, P., Short, W., Skolnik, PR., Steigbigel, RT., Tedaldi, EM., Ward, DJ., Wiznia, AA., Wright, DP.

Merck Research Laboratories: M. Nessly, J. Chen, A. Rodgers, J. Zhao, X. Xu, D. Hazuda, R. Isaacs, M. Miller, R. Danovich, R. Rhodes, B. Jackson, K. Strohmaier, P. Sklar, R. Leavitt, H. Teppler, B-Y. Nguyen.

Duke University: Jia Liu, Feng Gao, Charles Hicks, Nathan Vandergrift, Fangping Cai


Experimental approach

Use Parallel Allele-Specific Sequencing (PASS) to quantify specific RAL resistance-associated mutations (RAMs) present in baseline isolates

Focus on patients in BENCHMRK-2 who took RAL and had GSS = 0– BENCHMRK-2 had 45 RAL + OBT patients with GSS = 0– Data obtained for 32 patients: 14 virologic failures, 18 successes (48wk data)

Are minority resistant variants present at baseline?

If so, is their presence correlated with virologic failure?

Do viruses isolated from patients after virologic failure display the same mutations observed as minority variants at baseline?


N155H (66%) V151I (11%)

Detection of RAL resistance mutations in patient M010 after virologic failure (PASS method)

Liu, et al., Poster #685, CROI2009

Green = wild-type

Red = mutant


Mutations

Freq

uenc

y of

mut

atio

ns (

%)

Treatment success

Treatment failureAverage of frequency

0.001

0.01

0.1

1

10

Frequency of Minority Resistant Viruses in Each Patient

Q148R Q148K Q148H G140S L74M T97A G163R Y143C Y143H

Q148 pathway Y143 pathwayN155 pathway

Baseline RAL RAM detection in BENCHMRK-2 patients with GSS = 0 – no correlation with success/failure

Liu, et al., Poster #685, CROI2009


Minority RAL resistance mutations at baseline generally did not emerge after virologic failure (BENCHMRK-2

patients with GSS = 0) (Liu, et al., Poster #685, CROI2009)

N155H L74M E92Q T97A G163R Q148K Q148R Q148H G140S G140A Y143R Y143C Y143H

M010 105,000 3,640 0 0 0 0 1 (0.03) 0 0 0 1 (0.03) 0 0 0 0 N155H, V151I, E157Q M011 172,000 3,347 0 3 (0.09) 0 1 (0.03) 4 (0.12) 0 0 0 1 (0.03) 0 0 0 0 E92Q, T97T/A, Y143Y/H, N155N/HM017 160,000 2,018 0 1 (0.05) 0 0 3 (0.15) 0 0 0 0 0 0 0 0 N155H, T97A, L74M, S230R, Y143CM019 8,430 408 0 0 0 0 1 (0.25) 0 0 0 0 0 0 0 0 Q148H, G140SM020 34,300 836 0 0 0 0 0 0 0 0 0 0 0 0 0 N155N/H, Q148Q/R/H, V151V/I, G140SM023 36,800 525 0 0 0 0 1 (0.19) 0 0 0 0 0 0 0 0 N155H, Q148H, G140SM027 34,700 531 0 0 0 0 1 (0.19) 0 0 0 0 0 0 0 0 Q148R, G140S, D167D/NM031 27,700 621 0 0 0 0 0 0 0 0 1 (0.16) 0 0 0 0 Q148R/H, G140SM032 12,200 45 0 1 (2.22) 0 0 0 0 0 0 0 0 0 0 0 N155N/H, Q148Q/R, E138E/KM034 414,000 1,644 0 0 0 0 0 0 0 0 1 (0.06) 0 0 0 0 Q148H, G140SM035 18,900 349 0 0 0 0 0 0 0 0 0 0 0 0 0 N155N/H, Q148Q/RM036 132,000 705 0 0 0 0 0 0 0 0 1 (0.14) 0 0 0 0 N155H, Q148H, G140SM038 41,500 2,529 0 0 0 0 3 (0.12) 0 0 0 0 0 0 0 0 N155H, G163RM039 109,000 1,019 0 0 0 0 1 (0.10) 0 0 0 0 0 0 0 0 N155N/H, E92E/Q

M001 152,000 1,691 0 0 0 0 2 (0.12) 0 0 0 0 0 0 0 1 (0.06) Not doneM002 5,710 74 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM003 4,090 6 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM004 8,160 144 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM006 59,900 572 0 0 0 0 1 (0.17) 0 0 0 0 0 0 0 0 Not doneM007 134,000 1,000 0 0 0 1 (0.10) 0 0 0 0 0 0 0 0 0 Not doneM009 30,400 630 0 0 0 0 0 0 0 1 (0.16) 0 0 0 0 0 Not doneM012 750,000 12,015 0 1 (0.01) 0 2 (0.02) 13 (0.11) 1 (0.01) 1 (0.01) 0 1 (0.01) 0 0 1 (0.01) 1 (0.01) Not doneM014 241,000 978 0 0 0 0 3 (0.31) 0 0 0 1 (0.10) 0 0 0 0 Not doneM021 2,880 26 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM022 55,000 2,402 0 2 (0.08) 0 0 0 0 0 0 0 0 0 0 0 Not doneM024 5,430 3 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM025 99,100 1,551 0 1 (0.06) 0 0 1 (0.06) 0 0 0 1 (0.06) 0 0 0 0 Not doneM028 5,910 107 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM029 5,490 87 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM030 5,630 10 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM033 66,000 492 0 0 0 0 0 0 0 0 0 0 0 0 0 Not doneM037 111,000 14 0 0 0 0 0 0 0 0 0 0 0 0 0 Not done

Genotype

Failure

Success

PIDTreatment Viral load (copies/ml)

No. of genomes analyzed

N155 pathway Q148 pathway Y143 pathway


Conclusions from PASS study

Primary RAL resistance mutations (Y143, N155, Q148) were very infrequent in baseline viral isolates (<0.2% per patient) and did not correlate with subsequent virologic failure

Some secondary RAL resistance mutations were observed infrequently in baseline samples– Generally not correlated with virologic failure– Observed some examples of minority variants becoming more prevalent

after virologic failure

See poster by Liu, et al. (Poster #685) for complete story


Can minority RAL resistance variants be detected at baseline, and are they associated with treatment success or

failure?

Data from patients in Protocol 004 who received RAL monotherapy followed by combination therapy


Acknowledgments

PN004 InvestigatorsD. Baker

Australia

M. Bloch

Australia

N. Bodsworth Australia

D. Cooper Australia

C. Workman Australia

C. Kovacs Canada

C Tsoukas Canada

A. Afani Chile

J. Perez Chile

J. Cortes Colombia

G. Prada Colombia

E. Gotuzzo Peru

F. Mendo Peru

J. Morales-Ramirez Puerto Rico

J. Santana-Bagur

Puerto Rico

S. Brown

USA

C. Crumpacker

USA

C. Hicks

USA

P. Kumar

USA

K. Lichtenstein

USA

R. Liporace

USA

S. Little

USA

M. Markowitz

USA

R. Schwartz

USA

R. Steigbigel USA

K. Tashima

USA

W. Ratanasuwan Thailand

S. Thitivichianlert Thailand

H. Teppler

B.-Y. Nguyen

R. Isaacs

J. Zhao

H. Wan

J. Chen

L. Gilde

L. Wenning

M. Miller

D. Hazuda

J. Vacca

M. Rowley

V. Summa

M. Iwamoto

Merck

Special thanks to B. Taillon, B. Simen, L. Blake, and E. St John. (Roche/454 Life Sciences) for 454 sequence analyses

All patients who participated in PN004


Part I cohort Rx-naïve ptsstratified and randomized to Integrase monotherapy

or placebo for 10 days

MK-0518 600mg bid

MK-0518 400mg bid

MK-0518 200mg bid

MK-0518 placebo bid

MK-0518 600mg bid + TFV*/3TC

MK-0518 400mg bid+ TFV* /3TC

Part I

Integrase Monotherapy for 10 days

Part II

Combination Therapy

Interim analysis of Part I before initiating Part II

*TFV = tenofovir

~ 8pts

~ 8pts

~ 8pts

~ 8pts

~ 30 pts

~ 30 pts

~ 30 pts

~ 30 pts

MK-0518 200mg bid+ TFV*/ 3TC

Efavirenz 600mg** + TFV*/3TC

MK-0518 100mg bid~ 8pts ~ 30 pts

MK-0518 100mg bid + TFV*/3TC

Part II cohort Rx-naïve ptsstratified and randomized to combination therapy for 48

weeks

Total~ 38 pts

~ 38 pts

~ 38 pts

~ 38 pts

~ 38 pts

Protocol 004: Study Design


Protocol 004 – 96 weeksPercent of Patients (95% CI) With HIV RNA <50 Copies/mL

[Non-Completer=Failure]

*After Week 48 patients in all RAL groups continued at 400 mg b.i.d.All patients received TDF/3TC

m518p4 r50 7Manu_ July 17, 2008

39 39 3940 40 4041 41 41 160 160 159 16040 40 4038 37 38 38 38 38 38

Raltegravir 100 mg b.i.d.Raltegravir 200 mg b.i.d.Raltegravir 400 mg b.i.d.Raltegravir 600 mg b.i.d.Efavirenz 600 mg q.d.

0 4 8 16 24 32 40 48 60 72 84 96W eek

0

20

40

60

80

100 P

erce

nt o

f Pat

ient

s w

ithH

IV R

NA

<50

cop

ies/

mL

Number of Contributing Patients

Markowitz, et al., 2008, AIDS2008, Abstract #TUAB0102


Change From Baseline in Log10 HIV RNA (95% CI)†

(Protocol 004) (Cohort 1; Monotherapy Phase)

1 2 3 4 5 8 10Day

-3

-2

-1

0

1

Cha

nge

from

Bas

elin

ein

HIV

RN

A (L

og10

cop

ies/

mL)

Number of Contributing Patients7 7 7 7 5 7 77 7 7 7 6 7 76 6 6 6 6 6 68 8 8 8 7 8 87 7 7 7 4 7 7

m518p4 RNA10C1 Aug. 7, 2007

Raltegravir 100 mg BIDRaltegravir 200 mg BIDRaltegravir 400 mg BIDRaltegravir 600 mg BIDPlacebo

† Data as observed.HIV RNA of 1.7 – 2.2 log10 copies/mL (Markowitz et al., 2006 JAIDS 43:509)


Resistance analysis of patients enrolled in PN004 part I (RAL monotherapy): Ultradeep sequencing

Ultradeep sequencing (454 technology) used to detect emergence of low-level RAL resistance mutations before, during and after therapy

Focused on patients in 100mg and 200mg arms who later enrolled in part 2: samples available for 9 of 15 patients in these arms1. Baseline sample (pre-monotherapy)2. On-therapy sample – balance need for viral suppression (selective

pressure) and need for sufficient virus to obtain meaningful diversity– VL reduction from baseline: Mean = 1.4 log10; Range = 0.6 to 2.79 log10– VL at time of testing: Geo Mean = 1912; Range = 364 to 12,700

3. Baseline sample (pre-combination therapy) – – Time off RAL: Mean = 104 days; Range = 49 to 168 days


RAL RAMs detected by Ultradeep (454) sequencing in 9 patients receiving RAL monotherapy (100mg or 200mg

bid) in PN004

RAMs not detected in any sample (LOD = 0.4%): – N155H, Q148H, Q148K, Y143R, Y143C, L74M, E92Q, E138A, G140A

RAMs detected in BL samples:– Secondary mutation E138K in 1 patient (1.83% of sequences)– Secondary mutation S230R in 1 patient (3.16% of sequences)

RAMs detected on therapy:– Primary RAM Q148R detected in 1 patient (0.4% at day 10; VL = 364)– Secondary RAM G140S detected in 1 patient (3.04% at day 5; VL = 3460)


Results of Ultradeep (454) sequencing in 10 patients receiving RAL monotherapy (100mg or 200mg bid) in PN004

PATIENT Rx Group PART 2 FATE TIME POINT T97A E138K G140S Y143H Q148R V151I S230RA 200mg Success Baseline 0 0 0 0 0 0 0

On monotherapy 0 0 0 0 0 0 0Pre-Part 2 baseline 0 0 0 0 0 0 0

B 200mg Success Baseline 0 1.83 0 0 0 0 0On monotherapy 0 0 0 0 0 0 0Pre-Part 2 baseline 0 0 0 0 0 0 0

C 200mg Success Baseline 0 0 0 0 0 0 0On monotherapy 0 0 3.04 0 0 0 0Pre-Part 2 baseline 0 0 0 0 0 0 0

D 100mg Success Baseline 0 0 0 0 0 0 0On monotherapy 0 0 0 0 0 0 0Pre-Part 2 baseline 0 0 0 0 0 0 0

E 100mg Success Baseline 0 0 0 0 0 0 0On monotherapy 0 0 0 0 0 0 0Pre-Part 2 baseline 0 0 0 0 0 0 0

F 100mg Success Baseline 0 0 0 0 0 0 0On monotherapy 0 0 0 0 0 0 0Pre-Part 2 baseline 4.74 0 0 0 0 0 0

G 100mg Success Baseline 0 0 0 0 0 0 3.16On monotherapy 0 0 0 0 0.4 0 0Pre-Part 2 baseline 0 0 0 0 0 0 0

H 100mg Success Baseline 0 0 0 0 0 0 0On monotherapy 0 0 0 0 0 0 0Pre-Part 2 baseline 0 0 0 0 0 0 0

I 200mg Success Baseline 0 0 0 0 0 0 0On monotherapy 0 0 0 0 0 0 0Pre-Part 2 baseline 0 0 0 0 0 0 0

% of sequences with this mutation:


Disposition of patients who participated in PN004 Part I (10d monotherapy) at 96wks

PN004Part 1 (N = 35)

PlaceboN = 7

RAL 100mg bidN = 7

RAL 200mg bidN = 7

RAL 400mg bidN = 6

RAL 600mg bidN = 8

EFV + 3TC + TDF

N = 4

RAL 100mg bid+ 3TC + TDF

N = 6


N = 7


N = 6


N = 6

VF: 0/4Discon: 0/4

VF: 0/6Discon: 1‡/6

VF: 1†/7Discon: 1‡/7

VF: 0/6Discon: 2║/6

VF: 0/6Discon: 1‡/6

Part 1Enrollment

Part 2Enrollment

(N = 29)

Part 2Disposition

†No resistance to RAL, 3TC, or TDF at virologic failure (VF between 48 and 96 weeks)‡Viral load <50 copies/ml at discontinuation (4 patients) – all d/c’d between 48 and 96 weeks║Discontinued after 2 weeks of combination therapy (1 patient)


PN004 monotherapy conclusions 24 of 25 patients who received 10d RAL monotherapy were treatment

successes after 48 weeks of RAL+TDF+3TC combination therapy – The 1 patient with VF had NO resistance to RAL, TDF, or 3TC at VF – Low-level primary RAL resistance mutations appearing during PN004

monotherapy were rare (ultradeep sequencing) and did not result in virologic failure during the combination therapy phase.

– 1 patient selected Y143H during monotherapy, but did not enroll in part 2

RAL monotherapy did not reduce chance of treatment success

Different from NNRTI monotherapy study (DMP-266-003, cohort 1; Bacheler, et al., 2000, Antimicrob Agents Chemother. 44(9):2475-84)– EFV resistance detected in 11 of 16 patients after 2 weeks of EFV monotherapy– Higher failure rate among patients who received EFV monotherapy


Summary

Polymorphisms– 25 of 28 baseline polymorphisms analyzed to date had no significant

difference in frequency between virologic failures and treatment successes (exceptions: S17N, M50I, and D256E)--Further data needed to confirm

Minority variants– Primary RAL RAMs were detected at exceedingly low frequencies in

baseline samples: None detected by 454 sequencing (LOQ = 0.4%), frequencies of <0.2% were detected by PASS

– Primary RAL RAMs detected by PASS at baseline did not emerge in any patients who experienced virologic failure

– RAL resistance mutations appearing during PN004 monotherapy were rare, occurred at low levels, and did not result in virologic failure during the combination therapy phase.

1 © 2009 merck & co., inc., whitehouse station, nj usa. all rights reserved, emerging patterns...

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