antiretroviral therapy update 2016

Joseph J. Eron, Jr., MDProfessor of Medicine and EpidemiologyUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina

Antiretroviral Therapy Update 2016

Supported by educational grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck, and ViiV Healthcare.

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Disclosures

Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck, Roche Molecular Systems, Tibotec/Janssen, and ViiV and funds for research support (paid to the University of North Carolina) from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and ViiV.

When to Start ART

START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive Pts International, randomized phase IV study involving 215 sites in 35

countriesSerious AIDS and

Non-AIDS Events, n

42

96

Lundgren JD, et al. N Engl J Med. 2015;373:795-807.

Immediate ART(n = 2326)

Delayed ART(until CD4+ ≤ 350 cells/mm³)

(n = 2359)

Treatment-naive pts with CD4+ count

> 500 cells/mm³(N = 4685)

Study stopped by DSMB following results of interim analysis

– Overall HR: 0.43 (P < .001)

– HR for serious AIDS-related events: 0.28 (P < .001)HR for non-AIDS–related events: 0.61 (P = .04)

Similar HIV-1 RNA suppression rates 12 mos after starting ART in both arms (immediate: 98%; delayed: 97%)



START: Primary Endpoint Events by Latest CD4+ Cell Count

Latest CD4+ count > 500 cells/mm3

Immediate ART

Deferred ART

Primary events, % (n/N)

88(37/42)

59(57/96)

Rate/100 PY 0.6 1.1

Latest CD4+ Cell Count (cells/mm3)

< 35

035

0-49

950

0-64

965

0-79

9≥

800

< 35

035

0-49

950

0-64

965

0-79

9≥

800

Immediate ART Deferred ART

% o

f Fol

low

-up

Tim

e

60

50

40

30

20

10

0

2(4.7)

Pts With Events (Rates/100 PY)

Pts With Events (Rates/100 PY)

3(0.8)

6(0.4)

11(0.6)

20(0.6)

5(1.8)

34(2.0)

34(1.5)

9(0.6)

14(1.1)

Lundgren JD, et al. N Engl J Med. 2015;373:795-807. Slide credit: clinicaloptions.com


START: Cancer Events With Immediate vs Deferred ART

Cancer Event, nImmediate

ART(n = 2326)

Deferred ART

(n = 2359)Total 14 39Kaposi’s sarcoma 1 11

Lymphoma, NHL + HL 3 10

Prostate cancer 2 3

Lung cancer 2 2

Anal cancer 1 2

Cervical or testis cancer 1 2

Other types* 4 9

Time to Cancer Event

10

8

6

4

2

0Cum

ulat

ive

% W

ith E

vent

0 12 24 36 48 60Mos

*Immediate ART: squamous cell carcinoma, plasma cell myeloma, bladder cancer, fibrosarcoma. Deferred ART: gastric adenocarcinoma, breast cancer, ureteric cancer, malignant melanoma, myeloid leukemia, thyroid cancer, leiomyosarcoma, liver cancer, squamous cell carcinoma of head and neck.

Lundgren JD, et al. N Engl J Med. 2015;373:795-807.Lundgren J, et al. IAS 2015. Abstract MOSY0302.

Deferred ART

Immediate ART

Rate/100 PY: immediate, 0.20; deferred, 0.56(HR: 0.36; 95% CI: 0.19-0.66; P = .001)



HPTN 052: ART for Prevention of HIV Transmission in Serodiscordant Couples International, randomized, controlled trial

Stable, healthy, sexually active, HIV-discordant couples with CD4+ cell

count 350-550 cells/mm3 (N = 1763 couples)

Early ART ArmInitiate ART immediately

(n = 886 couples)

Delayed ART ArmInitiate ART at CD4+ cell count

≤ 250 cells/mm3 or at development of AIDS-defining illness

(n = 877 couples)

Grinsztejn B, et al. Lancet Infect Dis. 2014;14:281-290. Slide credit: clinicaloptions.com


HPTN 052: Reduced Risk of Partner Infection ART offered to all index pts in

delayed ART arm from May 2011 after interim results

8 linked HIV infections diagnosed after seropositive patient started ART

– All occurred before or soon after initiation or after virologic failure

No linked HIV transmissions observed when index participant stably suppressed on ART

Partner Infections, n (rate per 100 PY)

Overall (April 2005 - May 2015)

Early(4314 PY F/U)

Delayed(4180 PY F/U)

All 19 (0.44) 59 (1.41)Linked 3 (0.07) 43 (1.03)Risk Reduction With Early ART, %All infections 69 --Linked infections 93 --

Cohen MS, et al. IAS 2015. Abstract MOAC0101LB. Slide credit: clinicaloptions.com


What to Start

Comparison of Current International Guidelines for Treatment-Naive PtsRegimen DHHS[1] EACS[2] BHIVA[3] IAS-USA[4] GeSIDA[5]

DTG/3TC/ABC*

DTG + FTC/TDF

EVG/COBI/FTC/TDF†

EVG/COBI/FTC/TAF‡

RAL + FTC/TDF

ATV/RTV + FTC/TDF

DRV/RTV + FTC/TDF

EFV/FTC/TDF

RPV/FTC/TDF§

1. DHHS Guidelines. January 2016. 2. EACS HIV Guidelines. V 8.0. October 2015. 3. BHIVA Guidelines. 2015. 4. Günthard H, et al. JAMA. 2014;312:410-425. 5. GeSIDA. Enferm Infecc Microbiol Clin. 2013;31:602.e1-602.e98.

Recommended Alternative Not included

*Only if HLA-B*5701 negative. †Only if CrCl ≥ 70 mL/min. ‡Only if CrCl ≥ 30 mL/min. §Only if baseline HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3.



Continued Improvement in Currently Available ART Classes Dolutegravir

– Once-daily, unboosted integrase inhibitor

– Limited drug interactions, high barrier to resistance

– Use in renal dysfunction (CrCl down to 50 mL/min for DTG/3TC/ABC)

Tenofovir alafenamide– Equal efficacy with TDF-containing therapies, less bone toxicity and

renal tubular effects

– Smaller mg dosing (10 mg to 25 mg)

– Use in renal dysfunction (CrCl down to 30 mL/min) 2-drug therapy

– Less expensive, fewer toxicities?



Studies 104/111: Tenofovir Alafenamide vs TDF in Treatment-Naive Pts Parallel, randomized, double-blind, active-controlled phase III studies

– Primary endpoint: HIV-1 RNA at Wk 48

EVG/COBI/FTC/TAF*single-tablet regimen

(n = 866)

EVG/COBI/FTC/TDF†

single-tablet regimen(n = 867)

Treatment-naive pts with HIV-1 RNA ≥ 1000 c/mL,

eGFR ≥ 50 mL/min(N = 1733)

Stratified by HIV-1 RNA, CD4+ cell count, geographic region

Wk 481º endpoint Wk 144

*150/150/200/10 mg QD.†150/150/200/300 mg QD.

1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72:58-64.

HIV-1 RNA < 50 c/mL by FDA Snapshot

92%

90%

Difference (95% CI):

Wk 48[1] Wk 96[2]

+2.0% (-0.7 to +4.7)

+1.5% (-1.8 to +4.8)

86.6%

85.2%



TAF vs TDF: Change in Spine and Hip BMD Through Wk 96 by Age

More favorable proteinuria effects, smaller eGFR decline with TAF

Higher lipid levels with TAF due to absence of TDF lipid protective effect, but TC:HDL-C ratio same as TDF

Hip

All Ages DifferenceE/C/F/TAFE/C/F/TDF

Mea

n C

hang

es F

rom

Bas

elin

e B

MD

(%)

Difference in LSM

(%)

18-25 Yrs 18-25 Yrs

Wk Wk

Wohl D, et al. EACS 2016. Abstract LBBPD1/1.

Spine

All Ages


0

-1

-2

-3

-40

-1

-2

-3

-4

0

-1

-2

-3

-40

-1

-2

-3

-4

4

3

2

1

04

3

2

1

0

4

3

2

1

04

3

2

1

00 24 48 72 96 0 24 48 72 96


PADDLE: Dolutegravir + Lamivudine in Treatment-Naive Pts Open-label, single-arm phase IV exploratory trial

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (ITT-e, FDA snapshot analysis)

Figueroa MI, et al. EACS 2015. Abstract 1066.

Treatment-naive pts with HIV-1 RNA

5000-100,000 copies/mL; CD4+ cell count ≥ 200 cells/mm3;HBsAg negative

(N = 20)

Second Cohort

Dolutegravir 50 mg QD +Lamivudine 300 mg QD

(n = 10)

Dolutegravir 50 mg QD +Lamivudine 300 mg QD

(n = 10)

First Cohort

Second cohort to be enrolled following confirmation of

first cohort success at Wk 8



PADDLE: All Pts Virologically Suppressed by Wk 8 of Dolutegravir + Lamivudine Included 4 pts with HIV-1 RNA > 100,000 copies/mL at BL[1]

ACTG A5353: ph II (N = 120), single-arm, now enrolling (HIV-1 RNA < 500,000 c/mL) [2]

1. Figueroa MI, et al. EACS 2015. Abstract 1066. 2. Clinicaltrials.gov. NCT02582684.

Pt #HIV-1 RNA, copies/mL

Screen BL Day 2 Day 4 Day 7 Day 10 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 241 5584 10,909 3701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 502 8887 10,233 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 503 67,335 151,569 37,604 1565 1178 266 97 53 < 50 < 50 < 50 < 50 < 504 99,291 148,370 11,797 3303 432 179 178 55 < 50 < 50 < 50 < 50 < 505 34,362 20,544 4680 1292 570 168 107 < 50 < 50 < 50 < 50 < 50 < 506 16,024 14,499 3754 1634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 507 37,604 18,597 2948 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 508 25,071 24,368 6264 1377 Not done 268 105 < 50 < 50 < 50 < 50 < 50 < 509 14,707 10,832 Not done 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

10 10,679 7978 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 5011 50,089 273,676 160,974 68,129 3880 2247 784 290 288 147 < 50 < 50 < 5012 13,508 64,103 3496 3296 135 351 351 84 67 < 50 < 50 < 50 < 5013 28,093 33,829 37,350 26,343 539 268 61 < 50 < 50 < 50 < 50 < 50 < 5014 15,348 15,151 3994 791 198 98 < 50 61 64 < 50 < 50 < 50 < 5015 23,185 23,500 15,830 4217 192 69 < 50 < 50 < 50 Not done < 50 < 50 < 5016 11,377 3910 370 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 5017 39,100 25,828 11,879 1970 460 147 52 < 50 < 50 < 50 < 50 < 50 < 5018 60,771 73,069 31,170 2174 692 358 156 < 50 < 50 < 50 < 50 < 50 < 5019 82,803 106,320 35,517 2902 897 352 168 76 < 50 < 50 < 50 < 50 < 5020 5190 7368 3433 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50



Dolutegravir Monotherapy in Treatment-Naive Pts N = 9 pts who refused NRTIs and initiated DTG monotherapy

– All pts had baseline HIV-1 RNA < 100,000 copies/mL– No baseline NRTI, NNRTI, PI, or INSTI resistance

Lanzafame M, et al. J Acquir Immune Defic Syndr. 2016;72:e12-e14.

PtHIV-1 RNA, copies/mL CD4+ Cell Count, cells/mm3

Mos on DTGBaseline After 4 Wks’ DTG At Last Visit Baseline At Last Visit

1 20,400 Undetectable Undetectable 248 600 10

2 18,400 Undetectable < 20 335 471 9

3 90,500 31 Undetectable 356 527 7

4 39,000 35 Undetectable 350 623 7

5 43,300 < 20 Undetectable 329 613 7

6 17,500 45 < 20 229 404 6

7 18,200 < 20 Undetectable 785 879 6

8 16,900 Undetectable Undetectable 214 309 8

9 52,000 < 20 Undetectable 345 484 6



Switch Strategies

Reasons to Switch ART in Suppressed Pts

Simplification of complex therapies Improve tolerability and ease of administration Avoid or minimize drug–drug interactions Reduce toxicity or avoid future toxicity Change in clinical status

– Pregnancy or planned pregnancy, chemotherapy, organ transplant

Reduce costs or decrease copayments



Principles of Switching Therapy in Suppressed Patients Essential to get a complete ARV treatment history and resistance

tests results

– Archival HIV DNA resistance testing may be helpful

Maintain viral load suppression

– Complex history, missing information, and previous resistance increase risk

Within class switching likely has lowest risk

– TDF → TAF, EFV → RPV, RAL → DTG, RTV → COBI

Cross-class switching or from high to low barrier agents has greater risk

– b-PI → RPV, DTG → EVG, ETR → RPV (?)



STRIIVING: Switch From Suppressive ART to Fixed-Dose DTG/ABC/3TC Randomized, open-label phase IIIB study

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24– 12% to 13% of pts withdrew after randomization; ~ one half of withdrawals

were for protocol deviations

HIV-1 RNA < 50 copies/mL on stable ART ≥ 6 mos;

no previous virologic failure; HLA-B*5701 negative

(N = 551)

DTG/3TC/ABC(n = 274)

Wk 48Wk 24

Trottier B, et al. ICAAC 2015.

*Containing 2 NRTIs plus NNRTI, PI, or INSTI.

Baseline ART*(n = 277) DTG/3TC/ABC

PI NNRTI INSTI FTC/TDFBL ART use, % 42 31 26 77



STRIIVING: Outcomes at Wk 24

Switch to DTG/3TC/ABC noninferior to continued BL ART

Treatment difference (95% CI):

– ITT-exposed (E): -3.4 (-9.1 to 2.3)

– Per protocol (PP): -0.3 (-4.9 to 4.4)

No cases of protocol-defined virologic failure

– 3 pts in DTG/3TC/ABC arm (1%) and 4 pts in BL ART arm (1%) had HIV-1 RNA > 50 but < 100 copies/mL through Wk 24

10 pts discontinued for AEs in DTG/3TC/ABC arm vs 0 in baseline ART arm

However, significantly greater increase in treatment satisfaction score from baseline to Wk 24 in DTG/3TC/ABC arm vs baseline ART arm (P < .001)

Trottier B, et al. ICAAC 2015.

52

100

80

60

40

20

0VirologicSuccess

VirologicNonresponse

No Virologic Data

HIV

-1 R

NA

< 5

0 c/

mL

(%)

DTG/3TC/ABC (n = 274)Baseline ART (n = 277):DTG/3TC/ABC (n = 220)Baseline ART (n = 215)

85 8893 93

1410 61 1 < 1

ITT-E:

PP



GS-1089: Switch From Suppressive TDF- to TAF-Containing ART: Wk 48 Efficacy Randomized, double-blind, active-controlled phase III trial

– Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 by ITT FDA snapshot; noninferiority margin 10%

*FTC/TAF dosing: 200/10 mg with boosted PIs; 200/25 mg with unboosted third drug.

HIV-1 RNA < 50 c/mL at Wk 48, %

Gallant JE, et al. Lancet HIV. 2016;3:e158-e165.

Treatment difference: 1.3% (95% CI: -2.5% to 5.1%)

Switch FTC/TDF to FTC/TAF*Continue third ARV

(n = 333)

Continue FTC/TDFContinue third ARV

(n = 330)

HIV-infected pts withHIV-1 RNA < 50 c/mL,

eGFR ≥ 50 mL/min while receiving

FTC/TDF + third ARV(N = 663)

Wk 48 Wk 96

94.3

93.0



GS-1089: Renal and Bone Outcomes With Switch From TDF- to TAF-Containing ART Significant improvement in BMD and proteinuria

TAF

40

20

0

-20

-40

Med

ian

% C

hang

e at

Wk

48

Protein Albumin RBP β2-M

Urine Protein-to-Creatinine Ratio

7.7

-14.6-7.7

-16.3

-39.6

12.318.2 22.0

TDF

P < .001P < .001

P < .001

P < .001

Hip4

2

0

1.1

-0.2BL 24 48

Wks321317

309305

300303

P < .001

FTC/TAF, nFTC/TDF, n

No proximal renal tubulopathy or Fanconi syndrome in either arm

Mea

n %

Cha

nge

in B

MD

(95%

CI)

Gallant JE, et al. CROI 2016. Abstract 29.Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. Slide credit: clinicaloptions.com


New ART Strategies

LATTE-2: Cabotegravir IM + Rilpivirine IM for Long-Acting Maintenance ART Multicenter, open-label phase IIb study

– Primary endpoints: HIV-1 RNA < 50 c/mL by FDA snapshot at maintenance Wk 32, PDVF, and safety

Margolis DA, et al. CROI 2016. Abstract 31LB.

CAB 400 mg IM + RPV 600 mg IM Q4W(n = 115)

CAB 600 mg IM + RPV 900 mg IM Q8W(n = 115)

*Pts with HIV-1 RNA < 50 c/mL from Wk 16 to Wk 20 continued to maintenance phase. 6 pts discontinued for AEs or death in induction analysis.

ART-naive HIV-infected pts withCD4+ cell count > 200 cells/mm3

(N = 309) CAB 30 mg PO + ABC/3TC PO QD(n = 56)

CAB 30 mg PO QD + ABC/3TC

Wk 32primary analysis;

dose selection

Wk 20

Induction Phase* Maintenance Phase

Wk 1 Wk 96Wk 16: RPV PO added


LATTE-2: Maintenance Wk 32 Efficacy (ITT-Maintenance Exposed) and Safety No INSTI, NNRTI, or NRTI

resistance mutations detected Most frequent ISRs were pain

(67%), swelling (7%), and nodules (6%)– ISR events/injection: 0.53– 99% of ISRs grade 1/2; none

grade 4– 1% of pts withdrew for ISRs

Margolis DA, et al. CROI 2016. Abstract 31LB.

9594 91

4< 1 4 < 15 5

VirologicSuccess

VirologicNon-

response

No Virologic

Data

HIV

-1 R

NA

<50

c/m

L (%

) 100

80

60

40

20

0

IM CAB + RPV Q4W (n = 115)IM CAB + RPV Q8W (n = 115)Oral CAB + ABC/3TC (n = 56)

Treatment Differences (95% CI):Q8W IM vs Oral: 3.7 (-4.8 to 12.2)Q4W IM vs Oral: 2.8 (-5.8 to 11.5)

AEs, % Pooled IM Arms

(n = 230)

Oral Arm(n = 56)

Drug-related grade 3/4 AEs (excluding ISRs)

3 0

Serious AEs 6 5

AEs leading to withdrawal 3 2


LATTE-2: Wk 32 Pt Satisfaction With Maintenance Therapy vs Oral Induction

Pts

(%)

How satisfied are you with your current treatment?

100

80

60

40

20

0Q8W

(n = 106)Q4W

(n = 100)Oral CAB(n = 49)

More Neutral Less

100

80

60

40

20

0Q8W (n = 106)

Q4W (n = 100)

Oral CAB(n = 49)

More Neutral Less

How satisfied would you be to continue with your present form of treatment?

97 96 71

29

3 1

3

98 98 71

29

2 1

1

Margolis DA, et al. CROI 2016. Abstract 31LB. Slide credit: clinicaloptions.com

Doravirine + FTC/TDF vs EFV + FTC/TDF In Treatment-Naive Pts Doravirine: investigational NNRTI

with potent activity against common NNRTI RAMs, QD dosing, no PPI interactions, improved CNS safety vs EFV in early studies

Part 2 of 2-part randomized, double-blind phase II study in which ART-naive pts randomized to:

– Doravirine 100 mg QD + FTC/TDF (n = 66) or

– Efavirenz 600 mg QD + FTC/TDF (n = 66)

Current analysis also includes 85 pts who received these regimens in Part 1 of study

Gatell JM, et al. CROI 2016. Abstract 470.

78.777.877.8

81.573.172.9

57.5

63.0

42.1

26.9

47.2

27.8

12.015.7

100

80

60

40

20

0

Doravirine 100 mgEfavirenz 600 mg

0 4 8 12 16 20 24 28 32 36 40 44 48

Treatment Wk

Primary Endpoint:HIV-1 RNA < 40 c/mL (NC = F)

Wk 48 Difference (95% CI): -1.1 (-12.2 to 10.0)

Pts,

% (9

5% C

I)


Doravirine vs Efavirenz: Clinical AEs

Gatell JM, et al. CROI 2016. Abstract 470.

Clinical AEs, % DOR + FTC/TDF(n = 108)

EFV + FTC/TDF(n = 108)

Difference, DOR–EFV (95% CI)

≥ 1 AE 87.0 88.9 -1.9 (-10.9 to 7.1)

Serious AEs 6.5 8.3 -1.9 (-9.5 to 5.6)

Death 0 0

D/c for AEs 2.8 5.6 -2.8 (-9.2 to 3.0)

Drug-related AEs* 31.5 56.5 -25.0 (-37.3 to 11.8) Diarrhea 0.9 6.5 Nausea 7.4 5.6 Dizziness 6.5 25.9 Headache 2.8 5.6 Abnormal dreams 5.6 14.8 Insomnia 6.5 2.8 Nightmares 5.6 8.3 Sleep disorder 4.6 6.5

*Specific AEs occurring in > 5% of pts included. Slide credit: clinicaloptions.com

Attachment Inhibitor Clinical Development: BMS-663068 BMS-663068: prodrug of attachment inhibitor BMS-626529 HIV-1 variants have a range of susceptibility: in phase IIb study,

6% had BMS-626529 IC50 > 100 nM at screening Phase IIb study in participants with limited resistance [1]

– BMS-663068 (over range of doses) + RAL + TDF had similar activity over 48 wks vs ATV/RTV + RAL + TDF

Phase III study in highly ARV-experienced pts with MDR HIV [2]

– If at least 1 fully active ARV available, then– BMS-663068 600 mg or placebo BID for 8 days with no change in

background ART followed by BMS-663068 600 mg BID + OBR for ≥ 48 wks

– If no fully active ARV available, then– BMS-663068 600 mg BID + OBR for ≥ 48 wks

1. Feinberg J, et al. IDWeek 2015. Abstract 1075. 2. Clinicaltrials.gov. NCT02362503. Slide credit: clinicaloptions.com

Short-term Activity of a Maturation Inhibitor in Combination With a PI Randomized, multipart phase IIa trial

– BMS-955176: blocks viral maturation by inhib. cleavage between p24 and Gag SP1

HIV, subtype B–infected PI- and MI-naive pts

with HIV-1 RNA ≥ 5000 c/mL and CD4+ cell count ≥ 200 cells/mm3

(N = 28)

BMS-955176 40 mg QD + ATV 300 mg QD + RTV 100 mg QD

(n = 8)

BMS-955176 40 mg QD + ATV 400 mg QD (n = 8)

BMS-955176 80 mg QD + ATV 400 mg QD (n = 8)

Day 28*

ATV 300 mg QD + RTV 100 mg QD + FTC 200 mg QD/TDF 300 mg QD

(n = 4)

Max. Median Decline in HIV-1 RNA Through

Day 42 (log10 c/mL)

-2.02

-1.86

-2.23

-2.39

*Followed through Day 42.

No serious AEs or discontinuations for AEs; 1 grade 3/4 Tx-related AE in BMS-955176 80 mg + ATV 400 mg arm (transient neutropenia)

Hwang C, et al. IAS 2015. Abstract TUAB0106LB. Slide credit: clinicaloptions.com

MK-8591: Investigational NRTI With Potent Monotherapy Activity MK-8591: 4'-ethynyl-2-fluoro-2'-

deoxyadenosine[1]

– Active triphosphate exhibits prolonged intracellular half-life in vitro (> 72 hrs in PBMCs)

Open-label dose-ranging study in ART-naive pts[2]

– Single 10-mg MK-8591 dose(n = 6) suppressed HIV replication for at least 10 days

– AEs: headache (n = 6) and no other AE was seen in more than 1 participant

1. Stoddart CA, et al. Antimicrob Agents Chemother. 2015;59:4190-4198. 2. Friedman E, et al. CROI 2016. Abstract 437LB.

HIV-1 RNA Decrease Least-Squares Mean (95% CI)

Placebo (n = 20) -0.03 (-0.13 to 0.08)

MK-8591 10 mg (n = 6) -1.67 (-1.88 to -1.46)

-2.5

-2.0

-1.5

-1.0

-0.5

0

0.5

Log

HIV

-1 R

NA

Dec

reas

eHrs

0 50 100 150 200 250

Change in HIV-1 RNA Following Single 10-mg Dose of MK-8591


Conclusions

When to start– Pts should be started on ART regardless of CD4+ cell count

– HIV-related serious events including malignancy are more frequent in untreated vs treated pts with CD4+ cell counts > 500 cells/mm3

What to start– Simple, effective, well-tolerated regimens exist for initial therapy

including some for pts with moderate chronic kidney disease Switching ART in suppressed patients

– Many pts suppressed on older regimens can have therapy simplified

– Careful history taking and review of resistance testing are critical New therapies

– Long-acting ART and agents with new mechanisms of action are in late-stage clinical development


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