disclosures

Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials:• Baseline Survey

– Located at the front of your syllabus

• CME Evaluation with Post-activity Survey– Located at the back of your syllabus

Disclosures

• The relevant financial relationships reported by faculty that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

• The relevant financial relationships reported by the steering committee that they or their spouse/partner have with commercial interests are provided on page 5 of your syllabus

• The relevant financial relationships reported by the non-faculty content contributors and/or reviewers that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

Off-label Discussion Disclosure

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Learning Objectives

• Integrate recent clinical trial data into updated HIV management guidelines to provide the most individualized treatment for HIV-1-infected patients

• Develop a patient-centered approach to individualizing treatment for HIV by minimizing short- and long-term treatment-related complications

• Incorporate considerations about a patient’s risks for adverse events, non-adherence, and comorbid conditions when individualizing HIV treatments

Polling QuestionBaseline Survey

• Please take out the Baseline Survey from your packet• Fill out the demographic information at the top of the form;

then, throughout the program, as Baseline Survey questions are asked, please take a moment to select your answer to the corresponding question on this form

• Your answers are important and will help us shape and improve future CME activities:– Degree: ___ MD/DO ___ Nursing Professional ___ PharmD

___ Other:_____________________________

– Specialty: ___ Internist ___ Infectious Disease Specialist ___ PCP

___ Other: _____________________________


Please rate your confidence in your ability to individualize antiretroviral therapy for patients newly diagnosed with HIV-1

1. Not at all confident

2. Slightly confident

3. Confident

4. Very confident

5. Expert


How often do you consider a patient’s cardiovascular comorbidities when selecting an initial antiretroviral therapy for HIV-1?

1. Never

2. Rarely

3. Sometimes

4. Most of the time

5. Always


In a recent trial by HPTN 052, early initiation of ART was associated with which of the following outcomes compared to deferred initiation of therapy?

A. Decrease in mortality

B. Decreases in risk for transmission of HIV and development of AIDS-related conditions

C. Decrease in transmission of HIV, but no difference in AIDS-related conditions or mortality

D. Decreases in mortality, risk for transmission of HIV, and development of AIDS-related conditions

Case

• 58-year-old man with a new HIV diagnosis.

• Tested as part of an evaluation for prolonged viral syndrome, now recovered; previous negative test 8 months earlier.

• PMHx:

– Hypertension

– Diabetes

– Non-alcoholic steatohepatitis

– Stage III kidney disease (eGFR 30-59)

– Esophageal reflux

Case

• Medications: amlodipine, lisinopril, glipizide, metformin, simvastatin, pantoprazole.

• Social history: Works as a medical interpreter at a local hospital; MSM, in a long-term relationship (partner also newly diagnosed HIV+); 2-3 drinks/week; no cigarettes or other drugs.

• PE: BMI = 31; liver edge 2 cm below costal margin; 1+ bilateral edema.

Case

Labs

• Glucose = 185; HgbA1c = 7.9

• Creatinine = 1.6 (eGFR = 50, calculated creatinine clearance 61)

• ALT = 85, AST = 90; HBSAb positive, HCV antibody and RNA negative

• Total cholesterol 230 (non-fasting)

• U/A 1+ protein

• HLA-B*5701: Negative

• CD4 cell count = 780 (34%)

• HIV RNA = 45,000

• Genotype: No resistance


Would you treat?

A. Yes, as soon as possible

B. Yes, as soon as he is ready

C. Would focus on correcting metabolic issues first

D. Only if he has partners outside of relationship

E. Other


According to DHHS guidelines, all of the following antiretroviral regimens recommended for initial therapy might be appropriate for patient, EXCEPT:

A. Dolutegravir/ABC/3TC

B. Efavirenz/TDF/FTC

C. Elvitegravir/cobicistat/TDF/FTC

D. Raltegravir + TDF/FTC

CD4 Count (cells/mm3)

AIDS orHIV-related Symptoms <200 200-350 350-500 >500

United States DHHS (2014) Yes Yes Yes Yes Yes

IAS-USA (2014) Yes Yes Yes Yes Yes

British HIV Association (2013) Yes Yes Yes Consider Defer

European AIDS Society (2013) Yes Yes Yes Consider Consider

WHO (2013) Yes Yes Yes Yes Defer

When to Start HIV TherapyGuidelines Compared

DHHS. Available at: www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 1, 2014. IAS-USA. Gunthard HF et al. JAMA. 2014;312:410-425. EACS. Available at: www.europeanaidsclinicalsociety.org. Version 7.0 October 2013. BHIVA. Available at: www.bhiva.org. WHO. Available at: www.who.int/publications/guidelines/hiv_aids/en/index.html.

Earlier ART Associated with Decreased Mortality and Disease Progression Observational Studies

Study n Endpoint Relative Hazard or Hazard Ratio P or 95% CINA-ACCORD 8,362 Death 1.69

CD4 <350 vs 350-500<0.001

NA-ACCORD 9,155 Death 1.94 CD4 <500 vs >500

<0.001

When to Start Consortium

24,444 AIDS or Death

1.28 (HR)CD4 251-350 vs 351-400

1.04-1.57

HIV-CAUSAL 20,971 AIDS or Death

1.38 (HR)CD4 <350 vs <500

1.23-1.56

CASCADE 9,455 Death 0.51 (HR)CD4 350-499 vs deferred

0.33-0.80

COHERE 75,336 AIDS or Death

0.74 (HR)CD4 350-<500 on ART

0.96 (HR)CD4 ≥500 on ART

0.58-0.80

0.92-0.99

Kitahata MM et al. N Engl J Med. 2009;360):1815-1826. When To Start Consortium; Sterne JA et al. Lancet. 2009;373:1352-1363.HIV-CAUSAL Collaboration. Ann Intern Med. 2011;154:509-515. Writing Committee for the CASCADE Collaboration. Arch Intern Med. 2011;171:1560-1569. Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. PLoS Med. 2012;9:e1001194. .

0

0.05

0.1

0.15

0.2

0 1 2 3 4 5

Prevention of HIV-1 Infection with Early Antiretroviral Therapy• Randomized study of early vs delayed

ART in 1763 serodiscordant couples

• Study stopped early by DSMB

• Linked HIV transmission to HIV-negative partner

– Early therapy (n=1) – 0.1 per 100 person-years

– Delayed therapy (n=27) – 7 per 100 person-years

• Early ART led to a 96% reduction of sexual transmission of HIV in serodiscordant couples

Cum

ulat

ive

Prob

abili

ty

Linked HIV Transmission

EarlyART

DelayedART

Cohen MS et al. N Engl J Med. 2011;365:493-505.

Years

HR: 0.04(95% CI 0.01-0.27)

(P<0.001)

HPTN 052Early Treatment Delays AIDS Events

Number of Subjects Experiencing ≥1 EventDelayed Immediate

Tuberculosis 34 (4%) 17 (2%)Serious bacterial infection 13 (1%) 20 (2%)WHO Stage 4 event 19 (2%) 8 (1%)Esophageal candidiasis 2 2Cervical carcinoma 2 0Cryptococcosis 0 1HIV-related encephalopathy 1 0Herpes simplex, chronic 8 2Kaposi’s sarcoma 1 1CNS Lymphoma 1 0Pneumocystis pneumonia 1 0Septicemia 0 1HIV Wasting 2 0Bacterial pneumonia 1 2

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

875 825 445 166 31 29886 838 464 172 36 36

Time to First AIDS-Defining Disease

P=0.03

HIV Viremia Is Hazardous to Your Health

• Cumulative uncontrolled viral replication associated with all-cause mortality– 2027 patients contributing 6579 person-years of follow-up in a longitudinal cohort

of patients initiating ART from 2000-2008– Hazard ratio for mortality was 1.44 (1.07-1.94) per log10 copy y/mL– Stronger predictor of mortality than CD4 cell count

Mugavero MJ et al. Clin Infect Dis. 2011;53:927-935.

Months from antiretroviral therapy initiation0 6 12 18 24 30 36 42 48 54 60

1.00

.95

.90

.85

.80

.75

<55-7>7

Viremia copy-years (log 10)

Prop

ortio

n su

rvivi

ng

Treatment May be Deferred for Some

• Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence

• Patients may choose to postpone ART

• Providers may elect to defer ART, based on an individual patient’s clinical or psychosocial factors

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Revised August, 2014.

Special Cases – HIV Treatment Generally Indicated

• Pregnancy• Acute infection• Cardiovascular disease• Malignancies• HIV-associated nephropathy (HIVAN)• HBV/HCV co-infection• Neurologic complications• Serodiscordant relationships


Historical Trends in CD4 Thresholds for When to Start Antiretroviral Therapy

Adapted from Vittoria M.

ACTG 019 and other NRTI monotherapy studies in asymptomatic individuals

BW 002: ZDV reduces deaths in patients with AIDS

Disappointing results form Concorde, VA, & Delta Trials

MK 035 and ACTG 320 demonstrate virologic suppression and improved clinical outcomes: "Hit Hard and Early" Era and “HAART”

Lypodystrophy & other ARV-associated metabolic side effects described

Treatment reduces immune activation, non-AIDS events, & HIV transmission

Integrase inhibitors & 2nd-generation PIs/NNRTIs; single-tablet regimens

1st generation PIs & NNRTIs

(2 NRTIs)

Low potency and high toxicity Higher potency,

higher toxicity

Still greater potency, decreased toxicity.

HPTN 052

SMART study

Recommended Regimens for all VL strata

Recommended Regimens for VL < 100,000 c/mL Alternative Regimens

DHHS 2014 Guidelines: What to Start

*In HLA-B*5701–negative patients RPV is not recommended in patients with baseline HIV-1 RNA >100,000 copies/mL or CD4 <200‡EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl <70 mL/min.


NNRTI EFV/TDF/FTC EFV + ABC/3TC* RPV/TDF/FTC

Boosted PI

ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC ATV/RTV + ABC/3TC*

DRV/RTV + ABC/3TC* LPV/RTV + (TDF/FTC or

ABC/3TC*)

INSTI

RAL + TDF/FTC EVG/COBI/TDF/FTC‡

DTG + TDF/FTC DTG + ABC/3TC*

RAL + ABC/3TC*

Recommended Regimens Alternative Regimens

IAS-USA 2014 Guidelines: What to Start

* ABC has been associated with increased CV risk, although data are conflicting; use with caution in patients with high CV risk. Should only be used in HLA-B*5701-negative patients.

† Rilpivirine-based therapy is not recommended in patients with baseline HIV-1.€ The combination of abacavir and lamivudine was less efficacious with baseline HIV-1 RNA level above 100,000 copies/mL than the

combination of tenofovir and emtricitabine when combined with efavirenz or ritonavir-boosted atazanavir.

Gunthard HF et al JAMA. 2014;312:410-425.

NNRTI• EFV/TDF/FTC or• EFV + ABC/3TC*€

• RPV/TDF/FTC

• NVP + (TDF/FTC or ABC/3TC*)• RPV + ABC/3TC*

Boosted PI• ATV/RTV + (TDF/FTC or

ABC/3TC*€)• DRV/RTV + TDF/FTC

• ATV/COB + (TDF/FTC or ABC/3TC*)• DRV/COB + (TDF/FTC or ABC/3TC*)• DRV/RTV + ABC/3TC* • LPV/RTV + (TDF/FTC or ABC/3TC*)

INSTI• DTG + TDF/FTC• DTG + ABC/3TC*• ELV/COB/TDF/FTC• RAL + TDF/FTC

• RAL + ABC/3TC*

NRTI-sparing• DRV/RTV + RAL (only cd4>200, ? VL< 100K)• LPV/RTV + 3TC• LPV/RTV + RAL

NNRTI-based Regimens Long the Default First Choice, But Time for Reconsideration?

Strengths• One pill, once per day

– (TDF/FTC/EFV) Atripla and TDF/FTC/RPV (Complera)

• TDF/FTC/EFV– Effective across CD4/VL strata2

– Until recently, had never lost a head-to-head with another regimen6

– Longest clinical experience– Least expensive of recommended regimens

• TDF/FTC/RPV– Smallest pill size among single tablet regimens– Favorable metabolic profile

Weaknesses• High risk of resistance at virologic failure3

• Transmitted NNRTI resistance more common than other drug classes

• TDF/FTC/EFV- CNS/rash/hepatic effects1

- Concern for teratogenesis in first trimester4

- Dyslipidemia (LDL, Triglycerides)5

- Drug-drug interactions (including methadone)1

• TDF/FTC/RPV- More virologic failure with HIV RNA >100K or

CD4 <2007

- Must be taken with meal

- PPIs contra-inidicated

1. TDF/FTC/EFV [package insert]2. Ribaudo HJ et al. J Infect Dis. 2008;197:1006-1010.3. Gallant JE et al. N Engl J Med. 2006;354:251-260.4. Recommendations for Use of Antiretroviral Drugs in Pregnant

HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. www.aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/143/introduction. Updated March 2014.

5 Daar E et al. Ann Intern Med. 2011;154:445-456.6. Walmsley S et al. N Engl J Med. 2013;369:1807-1818.7. Molina JM et al. Lancet. 2011:378:238-246.

0 24 48 72 96 120 144 168 192

00.

010.

020.

030.

040.

05

EfavirenzEfavirenz-free

Weeks to Suicidality

Prob

abili

ty

Increased Risk of Suicidality Associated with EFV

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

*Person Years = sum of at-risk follow-up

As-treated HR 2.16 (1.16-4.00)

HR (95% CI)2.28 (1.27 to 4.10), P=0.006

47 events/5817 PY* (8.08/ 1000 PY)

15 events/4099 PY* (3.66/1000 PY)

5%

If you couldn’t (or didn’t want to) use an NNRTI-based regimen, which would you choose?

Differentiating Between Non-NNRTI Regimens


In ACTG study A5257, which compared raltegravir to darunavir/ritonavir and atazanavir/ritonavir, each with tenofovir/emtricitabine in treatment-naïve subjects, which of the following outcomes was reported?

A. Similar incidence of tolerability failure between all 3 groups

B. Greater virologic efficacy with atazanavir/ritonavir compared to raltegravir

C. Similar cumulative incidence of virologic or tolerability failure between all 3 groups

D. A higher rate of discontinuations due to toxicity with atazanavir/ritonavir compared to raltegravir


In addition to virologic outcomes, which of the following effects on cardiovascular risk was identified in the A5257 study:

A. Greater decreases in HDL-C with raltegravir compared to the protease inhibitors

B. No differences between groups in incidence of metabolic syndrome or lipid profile

C. Greater increases in triglycerides and LDL-C with the protease inhibitors compared to raltegravir

D. Greater incidence of new-onset metabolic syndrome with raltegravir compared to the protease inhibitors

ACTG A5257 Study Design*

RAL 400 mg BID + FTC/TDF 200/300 mg QD

n=603

DRV 800 mg QD + RTV 100 mg QD + FTC/TDF 200/300 mg QD

n=601

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

n=605

Study Conclusion 96 weeks after final participant enrolled

Follow-up continued for 96 weeks after randomization of last subject (range 2-4 years) regardless of status on randomized ART

Randomized 1:1:1 to Open Label TherapyStratified by screening HIV-1 RNA level (≥ vs < 100,000 c/mL) cardiovascular risk

*With the exception of RTV, all ART drugs were provided by the study

Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.

HIV-infected patients, ≥18 yr, with no previous ART, VL ≥ 1000 c/mL at US Sites, n=1809

Cum

ulat

ive

inci

denc

e

1.00

0.75

0.50

0.25

0.00

0 24 48 64 80 96 112 128 144

ATV/rRALDRV/r

Weeks since study entry

Cumulative Incidence of Virologic Failure


Difference in 96 wk cumulative incidence (97.5% CI)

-20 0-10 10 20

3.4% (-0.7%, 7.4%)

5.6% (1.3%, 9.9%)

-2.2% (-6.7%, 2.3%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

Cum

ulat

ive

inci

denc

e

1.00

0.75

0.50

0.25

0.00

0 24 48 64 80 96 112 128 144

ATV/rRALDRV/r



13% (9.4%, 16%)

3.6% (1.4%, 5.8%)

9.2% (5.5%, 13%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

-20 0-10 10 20

Cumulative Incidence of Tolerability Failure

Favors RAL

Favors DRV/r


Cum

ulat

ive

inci

denc

e

1.00

0.75

0.50

0.25

0.00

0 24 48 64 80 96 112 128 144

ATV/rRALDRV/r



-20 0-10 10 20

15% (10%, 20%)

7.5% (3.2%, 12%)

7.5% (2.3%, 13%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

Favors RAL

Favors RAL

Favors DRV/r

*Consistent results seen with TLOVR at a 200 copies/ml threshold

Cumulative Incidence of Virologic or Tolerability Failure


ATV/r RAL DRV/r1.0

1.6

0.4

0.2

0.0

0 24 48 64 80 96 120 144

ATV/rRAL

DRV/r

605603601

605603601

605603601

605603601

471483468

Number of subjects

contributing data

Proportion VL ≤50 copies/mLITT, regardless of ART change ITT, off-ART=failure (SNAPSHOT)

24 48 96 144

ATV/r 83% 90% 88% 90%

RAL 90% 92% 94% 94%

DRV/r 83% 88% 89% 90%

24 48 96 144

ATV/r 70% 73% 63% 62%

RAL 84% 83% 80% 76%

DRV/r 77% 77% 73% 71%

*Consistent results seen with TLOVR at a 200 copies/ml thresholdLandovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA. Abstract 85.

0.8

Study Week

Prop

of s

ubje

cts

w/H

IV-1

RN

A <=

50 c

opie

s/m

L ATV/r RAL DRV/r1.0

1.6

0.4

0.2

0.0

0 24 48 64 80 96 120 144

ATV/rRAL

DRV/r

605603601

563566564

553555542

515526518

394410387

Number of subjects

contributing data

Study WeekPr

op o

f sub

ject

s w

/HIV

-1 R

NA

<=50

cop

ies/

mL

Change in CD4 Count from Baseline

ATV/r: 284 (269,300)RAL: 288 (272, 304)DRV/r: 256 (240, 271)

Mean (95% CI)


ATV/r RAL DRV/r400

300

200

100

0 48 66 144 192

605603601

564565559

523541525

395418394

175179173

Number of subjects

contributing data0ATV/rRAL

DRV/r

Study Week

CD

4 co

unt c

hang

e fr

om b

asel

ine

(cel

ls/m

m3 )

Median (Q1-Q3)1000

750

500

250

0

-250

400

300

200

100

24 48 96 114 24 48 96 114 24 48 96 114

CD

4 co

unt c

hang

e fr

om b

asel

ine

(cel

ls/m

m3 )

ATV/RTV

Analysis of CIMT Progression

Stein JW et al. Presented at: ACC 2014, Abstract 147.

CCA CIMT Carotid Bifurcation CIMT

100

75

25

0

-25

0 48 96 144Study week

100

75

50

25

0

-25

0 48 96 144Study week

ATV RAL DRV

50

ATV RAL DRV

ATV/r vs DRV/r P=0.013

ATV/r vs RAL P=0.15

DRV/r vs RAL P=0.31

ATV/r vs DRV/r P=0.007

ATV/r vs RAL P=0.30

DRV/r vs RAL P=0.11

CIMT: Carotid intima media thickness

Take Home Messages from A5257/A5260s• Virologic suppression: RAL = DRV/r = ATV/r

• Tolerability: RAL=DRV/r > ATV/r– ATV/r discontinuations most commonly caused by cosmetic jaundice/hyperbilirubinemia

• Combined endpoints: RAL > DRV/r > ATV/r– Slightly better virologic outcomes and absence of GI side effects

• Lipids and bone mineral density loss favored RAL over both PIs– Increased fasting TC, non-HDL-C and LDL-C with ATV/r and DRV/r, while they

decreased or remained unchanged with RAL.

• CIMT progression most favorable with ATV/r– Mechanism unclear

Ofotokum I et al. Presented at: ACTG 5257 Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014; Boston, MA.

Brown T et al. Presented at: 2014 Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014; Boston, MA. Abstract 779LB.

SINGLE: ABC/3TC + DTG vs TDF/FTC/EFV for Treatment-naïve Patients

ABC/3TC FDC PO QD + DTG 50 mg PO QDTDF/FTC/EFV STR PLACEBO PO QHS

n=422

ABC/3TC FDC PLACEBO PO QD + DTG PLACEBO PO QDTDF/FTC/EFV STR PO QHS

n=422

HIV-infected treatment naïve men and women

VL >1000 c/mLn=844

PrimaryProportion <50 c/mL at 48 weeks

SecondaryTime to virologic suppressionChange in CD4SafetyResistance at virologic failure

Walmsley S et al. N Engl J Med. 2013;369:1807-1818.

SINGLE DTG + ABC/3TC Superior to EFV/TDF/FTC at Week 48

• DTG superior to EFV at week 48 primary efficacy endpoint

• 4% on each arm with protocol-defined VF

• Among pts with VF in EFV arm, 1 pt with NRTI, and 4 with NNRTI resistance vs 0 pts with resistance in DTG arm

• Treatment-related study discontinuation in 10% on EFV vs 2% on DTG

• CNS events and rash more common with EFV

HIV

-1 R

NA

< 50

c/m

L at

Wk

48 (%

) 8881

Difference 7.4%(95% CI: +2.5 to +12.3; P=0.003)

DTG 50 mg + ABC/3TC QD

(n = 414)

EFV/TDF/FTC QD (n = 419)

0

20

40

60

80

100

Walmsley S et al. N Engl J Med. 2013;369:1807-1818.

SPRING-2: 2 NRTIs + DTG vs 2 NRTIs + RAL for Treatment-naïve Patients

2NRTIs + DTG 50 mg PO QDRAL PLACEBO PO BID

n=411

2NRTIs + RAL 400 mg PO BIDDTG PLACEBO QD

n=411


VL >1000 c/mLn=822


Secondary Time to virologic suppression Change in CD4SafetyResistance at virologic failure

Stratified by baseline VL > or ≤100,000 c/mL and NRTI backbone

Raffi F et al. Lancet. 2013;381:735-743. Raffi F et al. Lancet Inf Disease. 2013;13:927-935.

• DTG non-inferior to RAL through 96 weeks

• Adverse events and discontinuation rates similar

• No resistance at VF with DTG vs 1 subject with integrase resistance and 4 with NRTI resistance in RAL group

DTG 50 mg QD (n = 411)RAL 400 mg BID (n = 411)

NRTIs: investigator chosen ABC/3TC (40%) or TDF/FTC 60%)

HIV

-1 R

NA

<50

c/m

L (%

)

88 85

0

20

40

60

80

100

8176

Wk 48 Wk 96

SPRING-2: Dolutegravir QD Non-inferior to Raltegravir BID Through Week 96

Raffi F et al. Lancet. 2013;381:735-743. Raffi F et al. Lancet Inf Disease. 2013;13:927-935.

FLAMINGO: DTG vs DTV/r for Treatment-naïve Patients

2NRTIs + DTG 50 mg PO QDn=243

2NRTIs + RTV 100 mg PO QD + DRV 800 mg PO QDn=245


VL >1000 c/mLn=488


SecondaryTime to virologic suppressionChange in CD4SafetyResistance at virologic failurePatient Reported Outcomes

Stratified by baseline VL > or ≤100,000 c/mL and NRTI backbone

Clotet B et al. Lancet. 2014;383:2222-2231.

FLAMINGO: DTG + NRTIs Superior to DRV/RTV + NRTIs at Week 48

• DTG superior to DRV/RTV (both with TDF/FTC or ABC/3TC) at week 48 primary efficacy endpoint

• VF: 2 pts (1%) on each arm

• No treatment-emergent resistance in either arm

• Treatment-related study discontinuation in 1% of DTG pts and 4% of DRV/RTV patients

• More diarrhea with DRV/RTV; more headache with DTGH

IV-1

RN

A <5

0 c/

mL

at W

k 48

(%)

Difference 7.1%(95% CI: +0.9 to +13.2; P = 0.025)

DTG 50 mg QD + NRTIs

(n = 242)

DRV/RTV 800/100 mg QD + NRTIs

(n = 242)

9083

0

20

40

60

80

100

NRTIs: investigator chosen ABC/3TC (33%) or TDF/FTC 67%)

Clotet B et al. Lancet. 2014;383:2222-2231.

Several Drugs Inhibit Tubular Secretion of Creatinine, Raising Serum Creatinine Levels

Proximal Tubule

Blood(Basolateral)

Urine(Apical)Active Tubular Secretion

Creatinine

ATP

H+

ATP

ATP

ATP-Binding

Cassette

Solute CarrierDolutegravir Cobicistat RitonavirCimetidineTrimethoprim

Lepist et al. Presented at: 51st ICAAC, Sep 17-20, 2011, Chicago, IL.

OCT2

No apparent effect on actual

GFR

Pgp

BCRP

MRP2

MATE1

MATE2-K

OCTN1

OCTN2

Phase III Studies of TDF/FTC/COB/EVG

vs NNRTI• Non-inferior to Efavirenz/TDF/FTC

Through Wk 144 – Consistent across subgroups

– Resistance at VF detected in 10 pts per arm

• In EVG/COB, 9/10 pts had primary integrase and 10/10 had NRTI resistance mutations

• In EFV, 10/10 had NNRTI and 3/10 had NRTI resistance mutations

• Renal safety– 13/701 discontinuation (1.9%), including 4 due

to proximal renal tubulopathy in EVG/COB

– No discontinuation in EFV

vs PI/r• Non-inferior to ATV/RTV +

TDF/FTC Through Wk 144– Consistent across subgroups

– In EVG/COB, resistance at VF detected in 6 pts through Wk 96 vs 0 pts in ATV/RTV arm

• 5/6 had primary integrase and 5/6 had NRTI resistance mutations

• Renal safety– 13/701 discontinuation (1.9%), including 4

due to proximal renal tubulopathy in EVG/COB

– 8/355 discontinuation (2.3%), including 3 due to proximal renal tubulopathy in ATV/RTVZolopa A et al. J Acquir Immune Defic Syndr. 2013;63:96-100.

Sax PE et al. Lancet. 2012;379:2439-2448.Wohl D et al. ICAAC 2013. Abstract H-672a.

Rockstroh J et al. J Acquir Immune Defic Syndr. 2013 63:77-85. De Jesus E et al. Lancet. 2012; 30:2429-2438.Cohen C et al. IAC 2014; Melbourne, Australia. Poster WEPE063.

Summary of Results from Tx-Naïve Phase III Studies of EVG/COB/TDF/FTC

• Virologic outcomes noninferior to EFV/TDF/FTC and ATV/RTV + TDF/FTC

– Activity sustained in high VL stratum

• 2% failed with resistance, usually to both NRTIs and EVG

• Adverse events

– vs EFV: fewer CNS, rash events; better lipids; more nausea

– vs ATV/RTV: less jaundice

• Small, rapid increase in serum creatinine related to cobicistat’s inhibition of tubular secretion of creatinine from inhibition of MATE-1 transporter

Important NRTI-sparing or NRTI-limiting StudiesStudy Design Outcome

ACTG 5142 LPV/r + 2NRTIs vs EFV + 2NRTIs vs LPV/r + EFV

More resistance on failure and lipid abnormalities with LPV/r + EFV

PROGRESS RAL vs TDF/FTC, both with LPV/r RAL non-inferior to TDF/FTC; baseline HIV RNA low in study population

ACTG 5262 DRV/r + RAL High rates of virologic failure in those with baseline HIV RNA > 100K

SPARTAN ATV BID + RAL BID vs TDF/FTC + ATV/r More virologic failure and jaundice in ATV + RAL arm

RADAR RAL vs TDF/FTC, both with DRV/r Higher rates of virologic failure with RAL + DRV/r

NEAT RAL vs TDF/FTC, both with DRV/rOverall non-inferior, but higher rates of virologic failure with RAL + DRV/r if baseline high HIV RNA or low CD4

GARDEL* 3TC vs 2 NRTIs, both with LPV/r 3TC non-inferior to 2 NRTIs, even at high HIV RNA

MODERN MVC vs TDF/FTC, both with DRV/r MVC inferior to TDF/FTC

Riddler SA et al. N Engl J Med. 2008;358:2095-106. Reynes J1 et al. HIV Clin Trials. 2011;12:255-267. Taiwo B1, et al. AIDS. 2011;25:2113-2122. Kozal MJ et al. HIV Clin Trials. 2012;13:119-130. Bedimo RJ et al. PLoS One. 2014;9:e106221. Raffi F et al. Lancet. 2014. [Epub ahead of print]. Cahn P et al. Lancet Infect Dis. 2014;14:572-580. Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.

*Only fully powered NRTI-limiting study to date demonstrating comparable efficacy and tolerability to standard-of-care regimens.

First-line Therapy: Special Situations

Sax PE. Key Principles and Recommended Regimens for First-line Antiretroviral Therapy. In “InPractice HIV” Eron JJ, Jr., MD; Kuritzkes DR; Squires, KE Editors; http://www.inpractice.com/Textbooks/HIV.aspx; Revised 9/8/14.

Patient Scenario Recommended Regimen Comment

Suboptimal adherence likely or possible

• Emtricitabine/tenofovir DF + atazanavir/ritonavir or darunavir/ritonavir

Lower risk of resistance at treatment failure with boosted Pls vs NNRTI- and RAL-based strategies.

HIV-1 RNA >100,000 copies/mL or CD4+ cell count <50 cells/mm3

• Efavirenz/emtricitabine/tenofovir DF• Emtricitabine/tenofovir DF +

atazanavir/ritonavir or darunavir/ritonavir• Emtricitabine/tenofovir DF + raltegravir• Cobicistat/elvitegravir/emtricitabine/

tenofovir DF• Emtricitabine/tenofovir DF + dolutegravir• Abacavir/lamivudine + dolutegravir

Specific regimens to avoid due to higher rates of virologic failure:

• Abacavir/lamivudine + efavirenz

• Abacavir/lamivudine + atazamavor/ritonavir

• Abacavir/lamivudine + rilpivirine

• Emtricitabinetenofovir DF + rilpivirine

http://www.inpractice.com/Textbooks/HIV.aspx




Hepatitis B co-infection

• Emtricitabine/tenofovir DF + any third drug listed as recommended

TDF/FTC provides 2 drugs active against hepatitis B, whereas other NRTI options (ABC/3TC and ZDV/3TC) have only 1, risking hepatitis B resistance to 3TC or FTC.

Hepatitis C co-infection • Emtricitabine/tenofovir DF + raltegravir

• Emtricitabine/tenofovir DF + dolutegravir• Abacavir/lamividine/dolutegravir

No significant drug-drug interactions between these agents and the HCV Pls telaprevir, boceprevir, and simeprevir. Note that sofosbuvir does not have significant drug-drug interactions with any HIV medication.






Sexually active women of childbearing potential not using reliable birth control

• Emtricitabine/tenofovir DF + boosted PI

Alternative antiretroviral regimens that do not include EFV should be strongly considered in women who 1) are planning to become pregnant or 2) are sexually active and not using effective contraception, assuming these alternative regimens are acceptable to the provider and are not thought to compromise the health of the woman. EFV may be continued in pregnant women receiving an EFV-based regimen who present for antenatal care in the first trimester, provided there is virologic suppression on the regimen.

Pregnancy • Emtricitabine/tenofovir DF + boosted PI

If patient becomes pregnant while on antiretroviral therapy, continue current regimen if virologic suppression has been achieved and if regimen is well tolerated.






Preexisting renal disease

• Abacavir/lamivudine/ dolutegravir

Patients with renal disease appear to be at greater risk of developing TDF-related renal dysfunction. If patients have both renal disease and are at high risk for cardiovascular disease (see below), some clinicians choose to use NRTI-sparing regimens suh as RAL or DTG + a boosted PI (several ongoing studies are evaluating these combinations).

ABC and 3TC must be given as separate agents in patients with eGFR < 50 mL/min as 3TC dose must be adjusted.

Low bone mineral density

• Abacavir/lamivudine/ dolutegravir

In 2 head-to-head clinical trials, TDF/FTC was associated with a greater decline in bone mineral density than ABC/3TC.






History of cardiac disease or multiple cardiac risk factors

• Efavirenz/emtricitabine/tenofovir DF

• Emtricitabine/tenofovir DF + atazanavir/ritonavir

• Emtricitabine/tenofovir DF + raltegravir

• Emtricitabine/rilpivirine/tenofovir DF• Emtricitabine/tenofovir DF +

dolutegravir• Cobicistat/elvitegravir/

emtricitabine/tenofovir DF

Several studies have suggested an increased risk of cardiovascular events in ABC- treated subjects; some studies have not found this association. A similar association has been found with some PIs (LPV/RTV, FpV/RTV, IDV).No association was found between ATV and MI risk; not enough data to date on DRV/RTV. If use of a Pl is necessary, ATV/RTV is preferred. RAL and DTG have a relatively neutral effect on plasma lipids. Among NNRTls, RPV has less effect on lipids than EFV.






Psychiatric disease


• Emtricitabine/tenofovir DF + raltegravir• Emtricitabine/rilpivirine/tenofovir DF• Cobicistat/elvitegravir/emtricitabine/

tenofovir DF• Emtricitabine/tenofovir DF + dolutegravir• Abacavir/lamivudine/dolutegravir

In general, EFV-related neuropsychiatric adverse effects are more difficult to tolerate in patients with active psychiatric disease, in particular depression. RAL may rarely cause psychiatric side effects, but does so less commonly than EFV. There are fewer CNS adverse effects with RPV, EVG, RAL, and DTG than EFV in clinical trials in treatment-naïve patients.

Transmitted NNRTI resistance


• Emtricitabine/tenofovir DF + raltegravir• Cobicistat/elvitegravir/emtricitabine/

tenofovir DF• Emtricitabine/tenofovir DF + dolutegravir• Abacavir/lamivudine/dolutegravir

Virologic response to NNRTI-based regimens markedly reduced when NNRTIs are used despite transmitted NNRTI resistance.





Case Study• 54-year-old man

– Obesity

– GERD, on PPIs

– Diabetes

– Creatinine 1.6 (calculated GFR 50)

– Dyslipidemia, on statin

– Transaminitis due to hepatic steatosis

– CD4 780

– VL 45,000

– WT genotype

– HLA-B*5701 negative


The case study patient has researched the topic and requests an integrase-based regimen with TDF/FTC. Your response is:

A. Ok

B. You prefer ABC/3TC, given renal disease

C. You prefer an “NRTI-sparing” or “NRTI-limiting” approach

D. Other

NNRTI-based Regimens Considered for This Case

Regimen Choices Considerations

TDF/FTC/EFV • May worsen dyslipidemia• Many other choices now with fewer CNS side effects

TDF/FTC/RPV • Contraindicated with pantoprazole

PI-based Regimens Considered for This Case

Regimen Considerations

TDF/FTC + DRV/r • May worsen dyslipidemia• No data yet on CV safety• Interacts with amlodipine, simvastatin

TDF/FTC + ATV/r • Combination of tenofovir with ATV/r may increase risk of TDF/FTC-associated renal disease

• Interacts with amlodipine, simvastatin• Must be dosed separately from pantoprazole

Integrase-based Regimens Considered for This Case

Regimen Considerations

TDF/FTC + RAL • RAL must be dosed twice-daily

TDF/FTC /EVG/COBI • Should not be used if GFR < 70• Interacts with amlodipine, simvastatin

TDF/FTC + DTG • Will slightly increase serum creatinine from DTG’s inhibition of tubular secretion of creatinine – could make monitoring of renal function more difficult

• DTG may increase levels of metformin; use with cautionABC/3TC + DTG • Has several significant cardiac risk factors

• DTG may increase levels of metformin; use with caution

Case Outcome

• Selection of the optimal ART regimen in this case required careful consideration of baseline cardiovascular, metabolic, and renal issues

• NRTI selection needed to balance possible nephrotoxicity of TDF with the potential cardiac toxicity of ABC; given ability to monitor for the former, TDF/FTC was selected

• For the key third drug, RAL and DTG were considered best – fewest drug interactions and favorable metabolic profile

• Although DTG is dosed once-daily and has a higher resistance barrier than RAL, its inhibition of creatinine secretion would make monitoring renal function more difficult, and the potential drug-drug interaction with metformin is a potential concern, particularly with impaired renal function

• Ultimately, TDF/FTC + RAL was selected

Conclusions

• HIV-infected patients are increasingly presenting for treatment with multiple medical comorbidities

• Choice of ART is now driven by additional considerations– No longer are virologic potency and tolerability sufficient– Important additional considerations now include:

• Cardiovascular risk

• Drug-drug interactions

• Effects on serum creatinine and nephrotoxicity

• Pill burden/availability of STR formulations

• Host genetics

• DHHS preferred regimens can be individualized based on traditional and new considerations with a nuanced understanding of regimen differences

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