what i use and why: expert strategies for selecting the best art regimen for each patient.2015

What I Use and Why: Expert Strategies for Selecting the Best ART Regimen for Each Patient

This activity is supported by an independent educational grant from ViiV.

clinicaloptions.com/hivEvidence-Based Strategies for Individualizing ART Regimens

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Faculty and Disclosure Information

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

Joseph J. Eron, Jr., MD, has disclosed that he has received funds for research support from GlaxoSmithKline/ViiV and Janssen and consulting fees from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline/ViiV, Gilead Sciences, Merck, Tibotec/Janssen, and Tobira.


Other Faculty Who Contributed to This ProgramDavid A. Cooper, MD, DScDirector, Kirby InstituteUniversity of New South WalesSydney, Australia

Eric S. Daar, MDChief, Division of HIV MedicineHarbor-UCLA Medical CenterProfessor of MedicineDavid Geffen School of Medicine at UCLALos Angeles, California

Sally Hodder, MD Director, Clinical Translation Science InstituteProfessor of MedicineWest Virginia UniversityMorgantown, West Virginia

Daniel R. Kuritzkes, MDChief, Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts

Anton L. Pozniak, MD, FRCPConsultant Physician Director of HIV Services Department of HIV and Genitourinary Medicine Chelsea and Westminster Hospital NHS Foundation Trust London, United Kingdom

Mark A. Wainberg, PhDDirector, McGill AIDS CentreMcGill UniversityMontreal, Quebec, Canada


Program Overview What I Use and Why – Series of case scenarios discussed

at recent IAS and ICAAC satellite symposia

– Patient cases addressing the following topics:

– When to start

– What to start

– Switching

Case 1: Young patient hesitant to start therapy


Patient History HH is a 34-year-old woman diagnosed with HIV 3 yrs ago

– Not ready to start treatment at that time

– Baseline CD4+ count: 1175 cells/mm3; HIV-1 RNA: 6125 c/mL

Current disease parameters:– CD4+ count: 995 cells/mm3, HIV-1 RNA: 17,525 c/mL

– No transmitted drug resistance

– HLA-B*5701: negative

– CBC, urea and electrolytes, liver function tests: normal

– HBV immune; HCV Ab negative

No significant medical history


Social History Husband died in South America 4 years ago of MDR TB

No children, no regular partner

– No sexual activity since HIV diagnosis

Has a sister living nearby, but the rest of her family resides in South America

She has missed several previous appointments, saying it is hard to get time off work, and she feels well anyway

What I Would Do and Why


What I Would Do On balance, I would initiate ART in this patient Considerations that support the decision to start:

– Clear data on benefits of early ART

– Labs suggest her HIV disease has progressed since time of diagnosis

– Potential for prevention of MDR-TB

– Prevention of onward HIV transmission Considerations that support waiting to start ART:

– Low event rate at high CD4+ cell counts

– Potential adherence concerns


START: Immediate vs Deferred ART International, randomized phase IV study: 215 sites in 35 countries

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)

Serious AIDS and Non-AIDS Events, n

42

96

Lundgren JD, et al. IAS 2015. Abstract MOSY0301. Lundgren JD, et al. N Engl J Med. 2015;[Epub ahead of print].

Immediate ART

Delayed ART(until CD4+ cell count

≤ 350 cells/mm³)

Treatment-naive pts with CD4+ cell count

> 500 cells/mm³

(N = 4685)


START: Serious AIDS and Non-AIDS Events

Components of the Primary Endpoint

Immediate ART(n = 2326)

Deferred ART (n = 2359)

HR (95% CI) P Valuen n/100 PY n n/100 PY

Serious AIDS-related event 14 0.2 50 0.72 0.28 (0.15-0.50) < .001

Serious non-AIDS–related event 29 0.42 47 0.67 0.61 (0.38-0.97) .04

Death from any cause 12 0.17 21 0.3 0.58 (0.28-1.17) .13

Tuberculosis 6 0.09 20 0.28 0.29 (0.12-0.73) .008

Kaposi’s sarcoma 1 0.01 11 0.16 0.09 (0.01-0.71) .02

Malignant lymphoma 3 0.04 10 0.14 0.3 (0.08-1.10) .07

Cancer not related to AIDS 9 0.13 18 0.26 0.5 (0.22-1.11) .09

Cardiovascular disease 12 0.17 14 0.2 0.84 (0.39-1.81) .65Lundgren JD, et al. IAS 2015. Abstract MOSY0301. Lundgren JD, et al. N Engl J Med. 2015;[Epub ahead of print].

68% of serious AIDS-related and non-AIDS–related events occurred in pts with CD4+ cell count > 500 cells/mm3


HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV transmission reduced by 93% with immediate ART (10-yr analysis)

Total HIV-1 Transmission Events: 78(19 in immediate arm and

59 in delayed arm)

Linked Transmissions: 46

Unlinked Transmissions: 32

P < .001

Immediate Arm: 3

Delayed Arm: 43

Cohen MS, et al. IAS 2015. Abstract MOAC0101LB.

No linked HIV transmission (from index participant to partner) occurred while index participant was receiving ART and had stable virologic suppression


HPTN 052: Decrease in AIDS-Related Events in Immediate vs Delayed ART Arms

Subjects Experiencing ≥ 1 AIDS-Related Event Delayed Immediate

Tuberculosis, n (%) 34 (4) 17 (2)

Severe bacterial infection, n (%) 13 (1) 20 (2)

WHO stage 4 event*, n (%) 19 (2) 9 (1)

Esophageal candidiasis, n 2 2

Cervical carcinoma, n 2 0

Extrapulmonary cryptococcosis, n 0 1

HIV-related encephalopathy, n 1 0

Herpes simplex (chronic), n 8 2

Kaposi’s sarcoma, n 1 1

Primary CNS lymphoma, n 1 0

Pneumocystis pneumonia, n 1 0

Recurrent septicemia, n 0 2

HIV wasting, n 2 0

Recurrent severe bacterial pneumonia, n 1 2

Non-AIDS events infrequent, with similar numbers of events in each arm

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

Time to First AIDS-Defining Disease

Logrank P = .031

Failu

re P

roba

bilit

y

Yrs Since Randomization0 51 2 3 4

.25

.20

.15

.10

.05

0

886875

829822

454435

169165

3531

3529

Immediate ARTDelayed ART

Pts at Risk, n

*Excluding tuberculosis.


When To Start Guideline Updates Reflect Latest Data ART now recommended for all HIV-infected pts worldwide,

regardless of CD4+ cell count

– Updated WHO guidance released September 2015[1]

DHHS ART guidance panel statement released July 2015, strengthening recommendation for initiating ART at any CD4+ cell count[2]

– “With the availability of the START and TEMPRANO trial results, the Panel’s overall recommendation remains the same: ART is recommended for all HIV-infected patients regardless of pre-treatment CD4 count. However, the strength of the recommendation will be changed to AI (strong recommendation based on data from randomized controlled trials) for all patients.”

1. WHO. Sept 2015. http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/. 2. DHHS ART Panel Statement. July 2015.

Case 2: Young, asymptomatic patient with no comorbidities


Patient History SH, a 28-year-old MSM who works as a lawyer for a bank

Diagnosed with HIV in 2012

Baseline disease parameters:

– CD4+ cell count: 895 cells/mm3

– HIV-1 RNA: 48,750 copies/mL



Current Presentation Current visit (September 2015):




– Complete blood count, urea and electrolytes, liver function tests: all normal


– Sexual health screen: negative; prior syphilis treated

You advise SH that he should start ART


Social History Compliant with regular 6 monthly visits and attends all of

his appointments

No current partner

Occasional cannabis, alcohol, nothing else recreational

Takes over-the-counter vitamins, minerals

No other medications

Has no preferences regarding type of ART regimen


What I Would Do Eligible for any of recommended regimens. Most would offer simplicity of single-

tablet regimen

– DTG/ABC/3TC

– EVG/COBI/TDF/FTC

– RPV/TDF/FTC

– I also keep DTG plus TDF/FTC on the list I discuss

Both ABC and TDF would be appropriate because he has no cardiovascular or bone/renal issues and he is HLA-B*5701 negative

My approach for this patient would be to have a discussion with him regarding his lifestyle and specific features of each of the regimens above (pill size, food requirements, potential future drug-drug interactions, etc.) to determine his preferences

– If he is unable to decide based on that discussion, I would recommend either DTG/ABC/3TC or DTG plus TDF/FTC


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

EFV/TDF/FTC

RPV/TDF/FTC

ATV/RTV + TDF/FTC

DRV/RTV + TDF/FTC

DTG/ABC/3TC

DTG + TDF/FTC

EVG/COBI/TDF/FTC

RAL + TDF/FTC

1. DHHS Guidelines. April 2015. 2. Günthard H, et al. JAMA. 2014;312:410-425. 3. EACS HIV Guidelines. V 8. October 2015. 4. BHIVA Guidelines. 2015. 5. WHO Guidelines. June 2013.

Preferred/recommended Alternative Not listed


Efficacy of Coformulated Regimens at Wk 48 Primary EndpointSingle-Tablet Regimen

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

Trials Considered

EFV/TDF/FTC 81-90 ACTG 5202[1]; GS 102[2]; STARTMRK[3]; SINGLE[4]; ECHO/THRIVE[5]; STaR[6]

RPV/TDF/FTC 84-86 ECHO/THRIVE[5]; STaR[6]

EVG/COBI/TDF/FTC 88-90 GS102[2]; GS103[7];

GS104/111[8]

DTG/ABC/3TC 86-90 SINGLE[4]; SPRING[9]; FLAMINGO[10]

1. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. Lennox JL, et al. Lancet. 2009;374:796-806. 4. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 5. Cohen C, et al. Lancet. 2011;378:238-246. 6. Cohen C, et al. AIDS. 2014;28:989-997. 7. De Jesus E, et al. Lancet. 2012;379:2429-2438. 8. Wohl DA, et al. CROI 2015. Abstract 113LB. 9. Raffi F, et al. Lancet. 2013;381:735-743. 10. Clotet B, et al. Lancet. 2014;383:2222-2231.


Most Widely Recommended Single-Tablet Regimens: Advantages & DisadvantagesRegimen Advantages DisadvantagesRPV/TDF/FTC[1,2] Compared with EFV

– Better tolerated– Reduced risk of

rash– Lipid neutral

Switch data available

Lower virologic efficacy for VL > 100K c/mL, CD4+ < 200 cells/mm3

Must be taken with food DDIs (including acid-reducing agents) DHHS: no longer among recommended first-

line therapies

EVG/COBI/TDF/FTC[3] Virologic efficacy Tolerability More clinical experience

than DTG/ABC/3TC Switch data available

Drug interactions Early Cr increase Cannot be used in pts with CrCl < 70 mL/min Must be taken with food Caution with divalent cations

DTG/ABC/3TC[4] Virologic efficacy Tolerability > EFV,

DRV/RTV Few drug interactions Lipid neutral Less resistance No meal restrictions

Mixed data on CVD risk with ABC Cannot be used in

HLA-B*5701–positive pts Early Cr increase Least experience in clinical practice Not sufficient for HBV Caution with divalent cations

1. RPV/TDF/FTC [package insert]. 2. DHHS Guidelines 2015. 3. EVG/COBI/TDF/FTC [package insert]. 4. DTG/ABC/3TC [package insert].


Drug-Drug Interaction and Food Considerations INSTIs

– Polyvalent cations should not be taken at the same time

– Exceptions: RAL can be taken with calcium carbonate antacids; DTG can be taken with calcium or iron supplements with food, or if separated 2 hrs before or 6 hrs after

Rilpivirine

– Must be taken with food

– Contraindicated in combination with proton pump inhibitors (eg, omeprazole)

– Caution and separate timing required for antacid or H2-receptor antagonist coadministration

Case 3: Older asymptomatic patient with diabetes and

hypertension


Patient History TM is a 58-year-old man with newly diagnosed

asymptomatic HIV infection

He has reasonably well-controlled hypertension and diabetes while taking the following medications:

– Metformin

– Sulfonylurea

– ACE inhibitor

Nonsmoker, occasional alcohol use

His father had MI at 62 years of age


Laboratory Parameters Baseline laboratories are as follows:

– Calculated creatinine clearance: 80 mL/min

– Urinalysis: 2+ proteinuria







What I Would Do The following regimens would be reasonable options:

– RAL + TDF/FTC– DTG*/ABC/3TC or DTG + TDF/FTC

– Note DTG may increase metformin levels when coadministered

– EVG/COBI*/TDF/FTC– Note COBI would likely increase DDI potential in an older patient with

comorbidities such as this

– DRV/RTV* or COBI* + TDF/FTC Based upon overall tolerability, convenience, and efficacy of

preferred options, I would use DTG + TDF/FTC with careful monitoring of renal function and dose reduction of metformin

*COBI, DTG, and to lesser extent RTV associated with reduced active secretion of creatinine in renal tubules leading to initial increases in creatinine levels after starting treatment.


Why I Eliminated Other Options Other INSTIs

– EVG and RAL both viable options which I would have strongly considered

NNRTIs– EFV has inferior tolerability and RPV is not an option for patients with

HIV-1 RNA > 100,000 copies/mL Boosted PI + TDF/FTC

– Potential for increased TDF toxicity with boosted PI and potentially not as well tolerated as DTG

ABC-containing options– I try to avoid ABC in patients with elevated CVD risk

ABC- and TDF-sparing regimens– Data limited


Studies Addressing Abacavir and MIStudy Association DescriptionD:A:D[1] Cohort collaboration (prospective)

Danish HIV Cohort[2] Cohort (linked with registries)

Montreal study[3] Nested case-control study

SMART[4] Post hoc subgroup analysis of RCT (use of ABC not randomized)

STEAL[5] Preplanned secondary analysis of RCT (use of ABC randomized)

Swiss HIV Cohort[6] Cohort (prospective)

FHDH ANRS CO4[7] ? Nested case-control study

NA-ACCORD[8] ? Cohort (retrospective)

VA Clinical Case Registry[9] X Cohort (retrospective)

Brothers et al analysis[10] X Post hoc meta-analysis of RCTs

ACTG A5001/ALLRT[11] X Post hoc meta-analysis of RCTs

FDA meta-analysis[12] X Post hoc meta-analysis of RCTs

1. Friis-Møller N, et al. N Engl J Med. 2003;349:1993-2003. 2. Obel N, et al. HIV Med. 2010;11:130-136. 3. Durand M, et al. J Acquir Immune Defic Syndr. 2011;57:245-253. 4. Phillips AN, et al. Antiviral Ther. 2008;13:177-187. 5. Martin A, et al. AIDS. 2010;24:2657-2663. 6. Young J, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 7. Lang S, et al. AIDS. 2010;24:1228-1230. 8. Palella F, et al. CROI 2015. Abstract 749LB. 9. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91. 10. Brothers CH, et al. J Acquir Immune Defic Syndr. 2009;51:20-28. 11. Ribaudo HJ, et al. Clin Infect Dis. 2011;52:929-940. 12. Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.


Tenofovir DF and Chronic Kidney Disease TDF has been associated with renal tubulopathy and

requires dose adjustment in patients with renal impairment

EVG/COBI/TDF/FTC should not be administered to patients with eGFR < 70 mL/min

TDF [package insert]. EVG/COBI/TDF/FTC [package insert].


TDF + Boosted PI and CKD Higher incidence of CKD among patients receiving TDF

+ PI vs TDF without a PI (IRR: 3.1 vs 1.3; P < .001)[1]

Greater decline in renal function among patients receiving TDF + PI vs TDF + NNRTI[2,3]

Higher incidence of renal events among women receiving TDF + LPV/r vs TDF + NVP (OR: 3.12; P = .019)[4]

1. Morlat P, et al. PLoS One. 2013;8:e66223. 2. Goicoechea M, et al. J Infect Dis. 2008;197:102-108. 3. Gallant JE, et al. AIDS. 2009;23:1971-1975. 4. Mwafongo A, et al. AIDS. 2014;28:1135-1142.


Comparing Integrase Inhibitors

Agent Advantages DisadvantagesRaltegravir Longest experience

Fewer drug interactions than EVG, DTG

Twice-daily dosing (for now) No coformulation

Elvitegravir Single-tablet regimen Once-daily dosing

Requires COBI boosting COBI drug interactions

similar to RTVDolutegravir The only non-TDF–

containing single-tablet regimen

Once-daily dosing Higher barrier to resistance Few drug interactions Active against some RAL-

and EVG-resistant virus

Coformulated with ABC/3TC only

Increases metformin levels


Wk 48

Wk 96

Wk 144

-5% 15%0

Favors EFV/TDF/FTC

Favors DTG+ABC/3TC

2% 14.6%

8.3%

7.4%

12.3%

8.0%

13.8%

2.5%

2.3%

-12% 25%0

Favors DRV/RTV

Favors DTG

7.1%

13.2%

12.4%

20.2%

0.9%

4.7%

-12% 12%0

Favors RAL

Favors DTG

2.4%

7.1%

4.5%

10%

-2.2%

-1.1%

HIV-1 RNA < 50 c/mL by Snapshot Analysis: 95% CI for Treatment Difference

SINGLE[1] FLAMINGO[2] SPRING-2[3]

1. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 2. Molina JM, et al. Glasgow HIV 2014. Abstract O153. 3. Raffi F, et al. Lancet. 2013;381:735-743.

Dolutegravir Phase III Trials in Treatment-Naive Patients


What if… he experienced progressive renal dysfunction during ART? TM was started on DTG + TDF/FTC with good tolerability

and viral suppression for the last 18 mos

Although DM and HTN remained controlled, he has experienced progressive decline in CrCl to 40-50 mL/min with stable 2+ proteinuria


What if… he experienced progressive renal dysfunction during ART? Switch to ABC + dose-adjusted 3TC + DTG

– Concern about ABC in patient with multiple cardiovascular risk factors

Switch to ABC- and TDF-sparing regimen

– Data for suppressed and treatment-naive patients with boosted PI alone and with 3TC

– Data for treatment-naive patients with boosted PI + INSTI

– Limited data in suppressed patients using INSTI + NNRTI


Multicenter, open-label phase III trial

GS-112: Switching to a TAF-Based Regimen in Pts With Renal Impairment

Gupta S, et al. IAS 2015. Abstract TUAB0103.

Virologically suppressed, HIV-positive pts with mild-moderate renal impairment (stable

eGFRCG [30-69 mL/min])(N = 242)

TDF-Based ART(n = 158)

Non-TDF–Based ART(n = 84)

EVG/COBI/FTC/TAF (N = 242)

Wk 96

PI NNRTI INSTI CCR5Antag. TDF ABC Other

NRTINo

NRTIART use,% 44 42 24 3 65 22 7 5

Wk 48Wk 24


GS-112: Key Results

Change in eGFR From Baseline to Wk 48

Actual GFR by Iohexol Clearance From Baseline to Wk 24

Gupta S, et al. IAS 2015. Abstract TUAB0103.

TDF Non-TDF

Med

ian

Cha

nge

From

Bas

elin

e

10

0

-10

+0.2

-1.8 -1.5 -2.7*

Baseline: 58 53 56 50eGFRCG

mL/mineGFRCKD-EPI Cr

mL/min/1.73 m2

*P < .05

Iohe

xol C

lear

ance

(mL/

min

)

BL Wk 2/4/8

Wk 24

63

50

62

48

63

49

0

20

40

60

80 Non-TDFTDF

BL Wk 2/4/8

Wk 24

GLSM Ratio vs BL (% [90% CI]):

98 (94-102)

100 (96-105)

96 (86-108)

98 (87-111)

Case 4: Woman with PCP and no available HIV resistance data


Patient History LW, a 32-year-old black woman presenting to the

emergency department

No past medical history except for 3 wks of tactile fevers, nonproductive cough, and increasing dyspnea on exertion

– Also reports 20-lb weight loss over the last 3 months

Physical exam shows oral thrush

Arterial blood gases show PO2 of 64 mmHg

Diagnosis of PCP confirmed


HIV Laboratory Parameters Rapid HIV test is positive and confirmed

HIV genotype is sent and pending

CD4+ cell count: 31 cells/mm3

HIV-1 RNA: 210,000 copies/mL

HLA-B*5701: negative

HBV immune


Clinical Course Patient is started on trimethoprim/sulfamethoxazole +

prednisone

During the first 5 days of hospitalization, the patient becomes afebrile and has decreasing shortness of breath

The patient is switched to oral medications, and after 7 days of hospitalization is prepared for discharge

– HIV genotype pending


What I Would Do I would start ART immediately with boosted DRV + NRTIs because:

– Randomized controlled ACTG 5164 trial showed reduced risk of new AIDS events or death in patients with PCP who received ART within 2 wks of diagnosis

– Very little evidence of transmitted resistance to boosted PIs with little risk of resistance even if there is transmitted NRTI resistance

– Once suppressed and genotype is back can always switch to simpler regimen

Alternative option would be DTG + TDF/FTC

– Transmitted INSTI resistance has been rarely reported

– Available data suggest higher genetic barrier to resistance with DTG than other INSTIs

– DTG generally better tolerated than boosted PIs


ACTG A5164: Reduced Risk of AIDS/Death With Immediate ART During Acute OI Median duration from start of

OI treatment to initiation of ART– Immediate group: 12 days

– Deferred group: 45 days

92% treatment naive– Median CD4+ count:

29 cells/mm3

– Median VL: 5.07 log10 c/mL

Safety and incidence of IRIS similar between groups

Patie

nts

Prog

ress

ing

to

AID

S or

Dea

th a

t Wk

48 (%

)

100

80

60

40

20

0

14.224.1

Immediate Deferred

P = .035

Zolopa AR, et al. PLoS One. 2009;4:e5575.


Prevalence of Drug-Resistance Mutations in Treatment-Naive Patients Baseline plasma samples

from 4 phase III trials 2000-2013 (N = 2531)[1]

– 1617 samples analyzed for integrase mutations

– 2531 analyzed for protease or RT mutations

– Little evidence of transmitted INSTI resistance

– Mostly T97A polymorphism

No transmitted INSTI resistance among 339 genotypic resistance tests from treatment-naive pts at 13 CA AIDS Healthcare Foundation sites Mar 2013 to Jun 2015[2]

1. Margot NA, et al. CROI 2014. Abstract 578. 2. Volpe JM, et al. ICAAC 2015. Abstract.

2000 (GS-903)2003 (GS-934)2013 (GS-104/GS-111)

0

2

NNRTI

10

4

6

8

NRTI PI INSTI

0.5 1.00

4.2

8.7

3.22.6 2.6

1.22.4

2.9

1.4


Low Virologic Failure and Treatment-Emergent Resistance With Boosted PIsTrial Name F/u,

WksTreatment Arm Virologic

Failure, n (%)Treatment-Emergent Primary Mutations, n

CASTLE[1] 96ATV/RTV + TDF/FTC (n = 440) 28 (6) 1 (PI), 7 (NRTI)

LPV/RTV + TDF/FTC (n = 443) 29 (7) 10 (NRTI)

ACTG 5202[2] 96ATV/RTV + NRTIs (n = 928) 140 (15) 1 (PI), 16 (NRTI)

EFV + NRTIs (n = 929) 129 (14) 68 (NNRTI), 36 (NRTI)

Study 103[3] 144ATV/RTV + TDF/FTC (n = 355) NR (7) 2 (NRTI)

EVG/COBI/TDF/FTC (n = 353) NR (8) 8 (INSTI), 8 (NRTI)

ARTEMIS[4] 96DRV/RTV + TDF/FTC (n = 343) NR (12) 2 (NRTI)

LPV/RTV + TDF/FTC (n = 346) NR (17) 5 (NRTI)

FLAMINGO[5] 96DRV/RTV + 2 NRTI (n = 242) 4 (2) 0

DTG + 2 NRTI (n = 242) 2 (< 1) 0

ACTG 5257[6] 96

ATV/RTV + TDF/FTC (n = 605) 95 (16) 1 (INSTI), 8 (NRTI)

DRV/RTV + TDF/FTC (n = 601) 115 (19) 1 (INSTI), 3 (NRTI)

RAL + TDF/FTC (n = 603) 85 (14) 1 (INSTI), 7 (NRTI),10 (INSTI + NRTI)

1. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 3. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124. 4. Mills A, et al. AIDS. 2009;23:1679-1688. 5. Molina JM, et al. Glasgow HIV 2014. Abstract O153. 6. Lennox JL, et al. Ann Intern Med. 2014;161:461-471.


Low Virologic Failure and Lack of Treatment-Emergent Resistance With DTG

Trial Name F/u, Wks Treatment Arm Virologic

Failure, n (%)

Treatment-Emergent

Primary Mutations, n

SPRING-2[1] 96DTG + 2 NRTI (n = 411) 22 (5) 0

RAL + 2 NRTIs (n = 411) 29 (7) 1 (INSTI), 4 (NRTI)

SINGLE[2] 144DTG + ABC/3TC (n = 414) 39 (9) 0

EFV/TDF/FTC (n = 419) 33 (8) 1 (NRTI), 6 (NNRTI)

FLAMINGO[3] 96DTG + 2 NRTI (n = 242) 2 (< 1) 0

DRV/RTV + 2 NRTI (n = 242) 4 (2) 0

Study 102[4] 144EVG/COBI/TDF/FTC (n = 348) NR (7) 9 (INSTI), 10 (NRTI)

EFV/TDF/FTC (n = 352) NR (10) 4 (NRTI), 14 (NNRTI)

Study 103[5] 144EVG/COBI/TDF/FTC (n = 353) NR (8) 8 (INSTI), 8 (NRTI)

ATV/RTV + TDF/FTC (n = 355) NR (7) 2 (NRTI)

1. Raffi F, et al. Lancet Infect Dis. 2013;13:927-935. 2. Pappa K, et al. ICAAC 2014. Abstract H-647a. 3. Molina JM, et al. Glasgow HIV 2014. Abstract O153. 4. Wohl DA, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e120. 5. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124.

Case 5: Suppressed on efavirenz, considering switch


Patient History MZ, 38-year-old male mental health nurse living in Los

Angeles

Receiving EFV/TDF/FTC for 1 year with viral suppression, but still struggles with dizziness, abnormal dreams, and chronic depression

Aware of new US and UK ART guidelines

– With more options now available, expresses interest in switching to another newer single-tablet regimen


Patient History (continued) Occasional alcohol, no other recreational substances

No other drugs/medicines


Disease and Lab Parameters Current disease and laboratory parameters:


– HIV-1 RNA: < 50 copies/mL


– Baseline drug resistance: not done

– Complete blood count, urea and electrolytes, liver function tests, chest x-ray: all normal

– HBV immune; HCV ab negative

– Sexual health screen: negative


What I Would Do I would switch this patient’s regimen to either EVG/COBI/TDF/FTC or

DTG/ABC/3TC

Concerns regarding long-term CNS effects of EFV

– Clinical trial data suggest association between EFV and suicidality but not confirmed to date in cohort analyses

Unlikely this patient will want to increase his pill burden

Studies of switch from EFV/TDF/FTC to RPV/TDF/FTC, EVG/COBI/TDF/FTC, or DTG/ABC/3TC have shown good maintenance of virologic suppression

Other potential switch option: coformulated DRV/COBI + 2 NRTIs, but no supporting data yet


2014-2015 Guidelines on Efavirenz for Treatment-Naive Pts DHHS[1]: Alternative

IAS-USA[2]: Recommended

WHO[3]: Recommended

EACS[4]: Alternative

BHIVA[5]: Alternative

1. DHHS Guidelines. April 2015. 2. Günthard H, et al. JAMA. 2014;312:410-425. 3. WHO Guidelines. June 2013. 4. EACS HIV Guidelines. V 8.0 October 2015. 5. BHIVA Guidelines. 2015.


Risk of Suicidality in Pts Treated With EFV-Containing Regimens in ACTG Trials Treatment with EFV associated

with increased risk of suicidality– Absolute risk is small

Risk of attempted or completed suicide also associated with EFV (HR: 2.58; 95% CI: 0.94 to 7.06; P = .065)

EFV also associated with increased risk of death from injury, substance use, or unknown causes

– Careful attention should be paid to cause of death in all clinical trials

HR: 2.28 (95% CI 1.27-4.10; P = .006)

47 events/5817 PY (8.08/1000 PY)

15 events/4099 PY (3.66/1000 PY)

Mollan K, et al. Ann Intern Med. 2014;161:1-10.

Multivariate Analysis of Factors Associated With Suicidality in ACTG Clinical Trials

Variable HR (95% CI) P Value

Randomly assigned EFV 2.15 (1.20-3.87) .01

Age category, yrs < 30 30-44 ≥ 45

2.82 (1.25-6.34) 1.69 (0.81-3.55) 1.00 (reference)

.04

Hx IDU 2.18 (1.11 -4.30) .02

Psychiatric hx or psychoactive rx 3.90 (2.23 -6.82) < .001

EFVEFV-free

0.05

0.04

0.03

0.02

0.01

0

Prob

abili

ty

1920 24 48 72 96 120 144 168Wks to Suicidality


Insurance claims data obtained from commercial insurance database and multistate Medicaid database

Suicidality determined by medical coding

Primary outcome: suicidality (coded as suicidal ideation or suicide attempt)

Secondary outcomes

– Suicide attempt (coded as suicide and self-inflicted injury)

– Injuries consistent with suicide attempt (coded as poisoning, open wounds, asphyxiation)

Adjusted HR for primary outcome of suicidality (vs EFV-free regimens)

– Commercial database: 1.03 (95% CI: 0.64-1.67)

– Medicaid database: 0.90 (95% CI: 0.62-1.32)

Nkhoma E, et al. IDWeek 2014. Abstract 646.

Real-World Assessment of Suicidality Risk Among Pts Initiating EFV


Principles of ART Switch Maintain viral suppression (do no harm or don’t mess up) Need to know beforehand:

– Previous ART history– Previously demonstrated or possible/probable ARV resistance based

on history – Drug-resistant virus remains archived in latently infected cells and does

not disappear even if not detected by resistance tests

– Likelihood of patient adherence to new regimen and its requirements– Patient acceptance of any new potential adverse effects– Other medications for potential DDIs– Affordability

Use available evidence to guide switch decisions


*P < .001†P < .01 (comparison with baseline within treatment group)

Subj

ect R

epor

ting

Sym

ptom

s (%

) HIV Symptom Index

Vivid Dreams Insomnia Anxiety Dizziness

100

136224

75212

65101

5687

119224

84209

48100

4187

103222

71208

40100

3487

90225

49211

3799

3287

BL Wk48 BLWk48 BL Wk48 BLWk48 BLWk48 BLWk48 BL Wk48 BL Wk48

Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.

STRATEGY-NNRTI: Outcomes in Pts Switching From EFV-Based Therapy

70605040302010

0

61

35*

64 6453

40†48 47 46

34†40 39 40 37 37

23*

EVG/COBI/TDF/FTCNNRTI + TDF/FTC

Switch noninferior to continued NNRTI regimen – Wk 48 HIV-1 RNA < 50 c/mL: 93% vs 88% (P

= .066)


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

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24

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

no previous virologic failure; HLA-B*5701 negative

(N = 551)

DTG/ABC/3TC(n = 274)

Wk 48Wk 24

Trottier B, et al. ICAAC 2015. Abstract.

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

Baseline ART*(n = 277)


Baseline ART use: PI 42%; NNRTI 31%; INSTI 26%; TDF/FTC 77%


STRIIVING: Switch to DTG/ABC/3TC Noninferior to Maintaining Baseline ART

No pt met criteria for protocol-defined virologic failure

D/c for AEs: 4% DTG/ABC/3TC vs 0 BL ART; grade 3/4 AEs: 3% DTG/ABC/3TC vs 2% BL ART; serious AEs: 2% in each arm

Small, nonprogressive serum Cr ↑ in DTG/ABC/3TC arm due to known DTG inhib. of tubular Cr secretion; no significant lipid changes in either arm

Significantly greater improvement in treatment satisfaction score with switch to DTG/ABC/3TC vs continuing BL ART

Trottier B, et al. ICAAC 2015. Abstract.

Outcomes at Wk 24, %ITT-Exposed Population Per Protocol Population


Baseline ART(n = 277)


Baseline ART(n = 215)

Virologic success 85 88 93 93

Virologic nonresponse 1 1 < 1 2

No virologic data 14 10 6 5

Treatment difference (95% CI) -3.4 (-9.1 to 2.3) -0.3 (-4.9 to 4.4)

Conclusion


Take-Home Points on First-line ART and Switch Strategies National/international guidelines on first-line ART changing

– Shifting away from NNRTIs

– Shifting toward INSTIs

– Still include some PIs Key principles for selecting among the available choices

– Convenience

– NRTI backbone

– Efficacy/safety/drug–drug interactions Primary focus when switching ART is maintaining viral

suppression

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what i use and why: expert strategies for selecting the best art regimen for each patient.2015

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