First and foremost choosing and using first line antiretroviral therapy.2013

First and Foremost: Choosing and Using First-line Antiretroviral Therapy

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clinicaloptions.com/hivFirst and Foremost: Choosing and Using First-line Antiretroviral Therapy

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Program Director

Daniel R. Kuritzkes, MD Chief, Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts


Faculty

Judith S. Currier, MD, MScProfessor of MedicineChief, Division of Infectious DiseasesDavid Geffen School of MedicineUniversity of California, Los AngelesLos Angeles, California

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

Paul E. Sax, MDClinical Director HIV Program and Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts

Kimberly Y. Smith, MD, MPHAssociate Professor of MedicineDivision of Infectious DiseasesRush University Medical CenterChicago, Illinois


Disclosures

Daniel R. Kuritzkes, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Celera, Gilead Sciences, GlaxoSmithKline, InnoVirVax, Merck, and Tobira; fees for non-CME services from Gilead Sciences and ViiV; and funds for research support from Gilead Sciences and Merck.

Judith S. Currier, MD, MSc, has disclosed that she has received consulting fees from Serono and ViiV and has received funds for research support from Merck.

Eric S. Daar, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from Bristol-Myers Squibb, Gilead Sciences, Merck, and ViiV.

Paul E. Sax, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, and Merck. Grants to Harvard Medical School have been received from Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline on his behalf.

Kimberly Y. Smith, MD, MPH, has disclosed that she has received consulting fees from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline/ViiV, Janssen, and Merck.

Initial Therapy: US Guidelines and Recent Clinical Trials


DHHS 2013 Guidelines: What to Start

DHHS Guidelines. February 2013.

Preferred Regimens Alternative Regimens

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

Boosted PI ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC

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

INSTI RAL + TDF/FTC RAL + ABC/3TC* EVG/COBI/TDF/FTC‡

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


IAS-USA 2012 Guidelines: What to Start

Recommended Regimens Alternative Regimens

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

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

Boosted PI ATV/RTV + (TDF/FTC or

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

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

ABC/3TC*)

INSTI RAL + TDF/FTC RAL + ABC/3TC*

EVG/COBI/TDF/FTC*In HLA-B*5701–negative patients with baseline HIV-1 RNA < 100,000 copies/mL. †Avoiding the use of ABC or LPV/RTV might be considered for patients with or at high risk of cardiovascular disease.

Thompson MA, et al. JAMA. 2012;308:387-402.


Initial Therapy Options: Important Differences Between DHHS and IAS-USA

IAS-USA[1] DHHS[2]

ABC/3TC (with EFV or ATV/RTV)

“Recommended” (provided BL HIV-1 RNA < 100k copies/mL)

“Alternative”

NVP (with ABC/3TC or TDF/FTC)

“Alternative” “Other”

1. Thompson MA, et al. JAMA. 2012;308:387-402. 2. DHHS Guidelines. February 2013.


Guidelines for Initial Therapy: Time for a Change? In 2009, DHHS listed 4

regimens as “preferred”; no changes since

Since then, several new agents have been approved: RPV, EVG/COBI, DTG

What do the clinical trials of these agents show?

Current Preferred Regimens

NRTIs Third Agent

TDF/FTC +

EFV

ATV/RTV

DRV/RTV

RAL


ECHO/THRIVE: Rilpivirine Noninferior to Efavirenz Through Wk 96

More virologic failures with RPV vs EFV: 14% vs 8%

– Difference due to more failures between Wks 0-48; failures comparable between arms from Wks 48-96

– Development of NRTI mutations more common with RPV vs EFV

– E138K mutation with RPV → cross-resistance with ETR

Discontinuation for AEs more common with EFV vs RPV: 9% vs 4%

RPV EFV

40

0

100

20

80 7878

60

682686n =

Pooled Data

HIV

-1 R

NA

< 5

0 c/

mL

at

Wk

96

(IT

T-T

LO

VR

)

Cohen CJ, et al. AIDS. 2013;27:939-950.


ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count

Cohen CJ, et al. AIDS. 2013;27:939-950.

HIV

-1 R

NA

< 5

0 co

pie

s/m

L (

%)

By Baseline CD4+ Count (cells/mm3)

84

71

≤ 100k

Rilpivirine Efavirenz

8076

> 100k -≤ 500k

56

71

< 50

6975

50 -< 200

81 7985

79

200 - < 350

≥ 350

By Baseline HIV-1 RNA (copies/mL)

0

20

40

60

80

100

0

20

40

60

80

100

n = 368 329 249 270 n = 34 36 194 175 313 307 144 164

65

73

69 83

> 500k


Open-Label STaR Trial: RPV/TDF/FTC Noninferior to EFV/TDF/FTC at Wk 48 RPV/TDF/FTC noninferior to EFV/TDF/FTC in overall population and in pts

with baseline HIV-1 RNA > 100,000 c/mL

– RPV/TDF/FTC superior to EFV/TDF/FTC in pts with baseline HIV-1 RNA ≤ 100,000 c/mL

Cohen C, et al. Glasgow 2012. Abstract O425.

8982

0

20

40

60

80

10086

All Pts VL ≤ 100k

82

RPV/TDF/FTC (n = 394)

EFV/TDF/FTC (n = 392)Δ: 4.1% (95% CI: -1.1 to 9.2)

80 82

VL > 100k

83 8272

80

VL > 100k - 500k

VL > 500k

Δ : 7.2% (95% CI: 1.1-13.4)

Δ : -1.8% (95% CI: -11.1 to 7.5)

Post Hoc Analysis

n/N =338/394

320/392

231/260231/260

204/250204/250

107/134107/134

116/142116/142

81/9881/98

96/11796/117

26/3626/36

20/2520/25


Summary of Results From Phase III Studies of RPV vs EFV More virologic failures, especially with HIV-1 RNA > 100k[1,2]

– Difference reduced in open-label study, suggesting importance of adherence, food effect[2]

– DHHS: RPV is not recommended in patients with pretreatment HIV-1 RNA > 100,000 copies/mL; higher rate of virologic failures reported in patients with pre-ART CD4+ count < 200 cells/mm3 who were treated with RPV + 2 NRTIs[3]

RPV resistance mutation (E138K) causes cross-resistance with ETR[1,2]

Fewer drug discontinuations with RPV than EFV[1,2]

– Fewer rash, CNS events; better lipids[1,2]

1. Cohen CJ, et al. AIDS. 2013;27:939-950. 2. Cohen C, et al. Glasgow 2012. Abstract O425. 3. DHHS Guidelines. February 2013.


Elvitegravir/Cobicistat/TDF/FTC Noninferior to Efavirenz/TDF/FTC Through Wk 144

Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, age, sex, race

Resistance at VF detected in 8 pts per arm through Wk 48, plus 2 additional pts per arm through Wk 96—rates similar btwn arms; no additional pts on EVG/COBI developed resistance after Wk 96

– In those on EVG/COBI, 9/10 pts had primary integrase and 10/10 had NRTI resistance mutations

– In those on EFV, 10/10 had NNRTI and 3/10 had NRTI resistance mutations

Zolopa 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.

Wk 48 Wk 144

EVG/COBI/TDF/FTC (n = 348)

EFV/TDF/FTC (n = 352)

8075

0

20

40

60

80

10088 84

Δ: 3.6% (95% CI: -1.6 to 8.8)

Δ: 4.9% (95% CI: -1.3 to 11.1)

8482

Wk 96

Δ: 2.7% (95% CI: -2.9 to 8.3)


EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 96

Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, adherence, age, sex, race

In EVG/COBI arm, resistance at VF detected in 5 pts through Wk 48, plus 1 additional pt through Wk 96 vs 0 pts in ATV/RTV arm

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

Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486.De Jesus E, et al. Lancet. 2012;379:2429-2438.

EVG/COBI/TDF/FTC (n = 353)

ATV/RTV + TDF/FTC (n = 355)

83 82

90

Wk 48 Wk 96

87

Δ: 2.7% (95% CI: -2.1 to 7.5)

Δ: 1.1% (95% CI: -4.5 to 6.7)

HIV

-1 R

NA

< 5

0 c/

mL

(%

)

0

20

40

60

80

100


Summary of Results From Tx-Naive Phase III Studies of EVG/COBI/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 inhibition of tubular secretion of creatinine

5 pts (0.7% of total) developed tubulopathy, likely from TDF


SPRING-2: Dolutegravir QD Noninferior to Raltegravir BID Through Wk 96

DTG noninferior to RAL at Wk 48[1] and Wk 96[2]

– Response similar with either NRTI pair and across VL strata

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

88 85

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

HIV

-1 R

NA

< 5

0 c/

mL

(%

)

0

20

40

60

80

100

8176

Wk 48 Wk 96

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

Raffi F, et al. Lancet. 2013;381:735-743. Raffi F, et al. IAS 2013. Abstract TULBPE17.


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

DTG superior to EFV at Wk 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

< 5

0 c/

mL

at

Wk

48 (

%)

8881

Difference 7.4%(95% CI: +2.5 to +12.3; P = .003)

Walmsley S, et al. ICAAC 2012. Abstract H-556b.

DTG 50 mg + ABC/3TC QD

(n = 414)

EFV/TDF/FTC QD

(n = 419)

0

20

40

60

80

100


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

DTG superior to DRV/RTV (both with TDF/FTC or ABC/3TC) at Wk 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 pts

More diarrhea with DRV/RTV; more headache with DTG

HIV

-1 R

NA

< 5

0 c/

mL

at

Wk

48 (

%)

9083

Difference 7.1%(95% CI: +0.9 to +13.2; P = .025)

Feinberg J, et al. ICAAC 2013. Abstract H1464a.

DTG 50 mg QD + NRTIs

(n = 242)

DRV/RTV 800/100 mg QD + NRTIs

(n = 242)

0

20

40

60

80

100


Summary of Results From Tx-Naive Phase III Studies of DTG DTG + NRTIs noninferior to RAL + NRTIs; superior to DRV/RTV +

NRTIs; DTG + ABC/3TC superior to EFV/TDF/FTC

– More drug discontinuations in EFV and DRV/RTV arms

No DTG resistance mutations as yet detected with virologic failure

DTG well tolerated with low rates of study drug discontinuation

– Fewer CNS and rash events compared with EFV

– Less diarrhea than DRV/RTV

Small rapid increase in serum creatinine related to inhibition of tubular secretion of creatinine

– No drug-related renal events


Dolutegravir Approval—August 2013

Dolutegravir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children aged 12 yrs and older and weighing at least 40 kg

– Dolutegravir 50 mg QD in treatment-naive or INSTI-naive treatment-experienced patients

– Dolutegravir 50 mg BID in INSTI-experienced patients or when administered with certain UGT1A/CYP3A inducers

Not yet included in guidelines

Dolutegravir [package insert].


Potential Benefits of New Treatment Options for HIV

Rilpivirine Elvitegravir/Cobicistat Dolutegravir

Smallest single-tablet regimen

Fewer CNS and rash events vs EFV

Better lipids than EFV Superior to EFV if HIV-1

RNA < 100k

Single-tablet regimen Maintains comparable

virologic activity to EFV, ATV across low and high HIV-1 RNA


Better lipids than EFV, comparable to ATV/RTV

Less jaundice than ATV/RTV

Superior to EFV/TDF/FTC and DRV/RTV

Maintains at least comparable virologic activity to EFV, RAL, DRV/RTV across low and high HIV-1 RNA


Better lipids than EFV No resistance detected

with virologic failure Fewer drug–drug

interactions than boosted PIs, EVG/COBI

Making the Match


2013 Recommendations for ART Initiation

ART is recommended for all HIV-infected ART-naive pts to reduce risk of disease progression and transmission

– Strength of recommendation varies by CD4+ cell count and risk group (perinatal, heterosexual, other)

– Pts should be ready to commit to ART and understand benefits and risks of therapy and importance of adherence; individual pts may elect to defer ART

Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug–drug interaction potential, resistance testing results, and comorbid conditions



Considerations When Selecting First-line Antiretroviral Therapy

Baseline CD4+ cell count/HIV-1 RNA level

Age

Sex

Occupation (eg, work schedule)

Comorbid conditions (eg, CV risk, renal abnormalities)

Plans for pregnancy

Access to care

Concurrent medications

Adherence to other medications

Genetics (eg, HLA-B*5701)

Viral tropism

Patient/Viral Factors Antiretroviral Drug Factors

Efficacy

Baseline drug resistance

Tolerability

Long-term toxicity/metabolic effects

Drug–drug interactions

Dosing frequency

Pill burden

Pharmacokinetics

Cost


Which Patient for EFV?

Considerations in Favor

Coformulation; 1 pill QD[1]

Effective across HIV-1 RNA, CD4+ strata[2]

Most experience of all NNRTIs

Most experience of all preferred drugs

Considerations Against

High risk of resistance at virologic failure[3]

CNS effects[1]

Potential for teratogenesis in early pregnancy[4]

Drug–drug interactions with other drugs metabolized by CYP system[1]

Increases in lipids[5]

1. TDF/FTC/EFV [package insert]. 2. Ribaudo HJ, et al. J Infect Dis. 2008;197:1006-1010. 3. Gallant J, et al. N Engl J Med. 2006;354:251-260. 4. DHHS Perinatal Guidelines. July 2012. 5. Daar E, et al. Ann Intern Med. 2011;154:445-456.


DHHS Guidelines: Using EFV in Pts Who Are (or Are Likely to Become) Pregnant ARV regimens that do not include EFV should be

strongly considered in women who

– Are planning to become pregnant or

– Are sexually active and not using effective contraception

Avoid initiation of EFV or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother throughout the pregnancy

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

DHHS Perinatal Guidelines. July 2012.


Which Patient for Boosted PIs?


Effective across HIV-1 RNA, CD4+ strata[1,2]

Few CNS adverse events[1,2]

Little/no emergence of resistance at VF[1,2]

Preferred agents in pregnancy (ATV/RTV, LPV/RTV)[3]

Low risk for new resistance to develop in those with transmitted resistance


No coformulations with NRTIs

Variable lipid effects[1,2]

Concerns about renal function (greatest concern when ATV/RTV combined with TDF)[1,4]

Drug–drug interactions with other drugs metabolized by CYP system[5,6]

Hyperbilirubinemia with ATV[1,5]

1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Ortiz R, et al. AIDS. 2008;22:1389-1397. 3. DHHS Perinatal Guidelines. July 2012. 4. Mocroft A, et al. AIDS. 2010;24:1667-1678. 5. Atazanavir [package insert]. 6. Darunavir [package insert].


DHHS Guidelines on ART for Patients With Early Infection Patients with early infection should be offered ART

– “Early” HIV infection now refers to acute (after infection, prior to seroconversion) and recent (< 6 mos) infections

– Choice of regimen should be among those recommended for patients with chronic disease

– ART can be initiated before drug resistance test results are available; if so, a boosted PI + 2 NRTIs should be chosen



Which Patient for RAL?



Few adverse events[1]

Few drug–drug interactions[2]

Limited effects on lipids[3]

Most experience of all INSTIs


No coformulations with NRTIs

Twice-daily dosing[2,4]

High risk of resistance at VF[3]

1. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85. 2. Raltegravir [package insert]. 3. Lennox J, et al. Lancet. 2009;374:796-806. 4. Eron JJ Jr, et al. Lancet Infect Dis. 2011;11:907-915.


Which Patient for TDF/FTC?



Not shown to be associated with MI in D:A:D[2]

Coformulations with EFV, EVG, RPV

Active against HBV[3]


Associated with decreases in renal function[4]

Associated with greater decreases in BMD[5]

1. Sax P, et al. N Engl J Med. 2009;361:2230-2240. 2. Worm S, et al. J Infect Dis. 2010; 201:318-330. 3. DHHS Guidelines. February 2013. 4. Gallant J, et al. AIDS. 2008;22:2155-2163. 5. McComsey G, et al. J Infect Dis. 2011;203:1791-1801.


Which Patient for ABC/3TC?


No specific association with decreases in renal function

Less decrease in BMD than with TDF[1]


No current coformulations

Less effective at HIV-1 RNA > 100,000 with EFV and ATV/RTV[2]

Associated with acute MI in some studies[3-5]

Requirement for HLA-B*5701 test before use[6]

Not optimal as lone NRTI pair in HBV-coinfected pts

1. McComsey G, et al. J Infect Dis. 2011;203:1791-1801. 2. Sax P, et al. N Engl J Med. 2009;361:2230-2240. 3. Worm S, et al. J Infect Dis. 2010; 201:318-330. 4. Martin A, et al. Clin Infect Dis. 2009;49:1591-1601. 5. Durand M, et al. J Acquir Immune Defic Syndr. 2011;57:245-253. 6. ABC/3TC [package insert].

What About the Newer Drugs?


Which Patient for RPV?


Coformulated/1 pill dailySuperior vs EFV at lower VL[1]

Fewer CNS adverse events than EFV[2]


Less effective at high BL VL[2] (not recommended at high VL and low CD4+)[3]

Food requirement[4]

Restricted use with PPIs or H2 blockers[4]

High risk of resistance and cross-resistance with other NNRTIs at VF[2]

1. Cohen C, et al. Glasgow 2012. Abstract O425. 2. Cohen C, et al. AIDS. 2013;27:939-950. 3. DHHS Guidelines. February 2013. 4. TDF/FTC/RPV [package insert].


Which Patient for TDF/FTC/EVG/COBI?


Coformulated/1 pill dally

Once-daily INSTI regimen

Noninferior to EFV and ATV/RTV across HIV-1 RNA, CD4+ strata[1,2]

Fewer CNS AEs than EFV[1]


Includes pharmacologic booster

High risk of resistance at VF[1-4]

Cross resistance with RAL[5]

Drug–drug interactions[6]

Concerns about monitoring renal function with COBI[6]

1. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 3. Sax PE, et al. Lancet. 2012;379:2439-2448. 4. DeJesus E, et al. Lancet. 2012;379:2429-2438. 5. DeJesus E, et al. IAS 2007. Abstract TUPEB032. 6. TDF/FTC/EVG/COBI [package insert].


Which Patient for DTG?


Once-daily INSTI without boosting

Superior efficacy vs EFV and DRV/RTV[1,2]

Potentially less resistance at VF[1,3]

Effective at high VL with both ABC/3TC and TDF/FTC[3]

Well tolerated[1-3]

Few drug–drug interactions[4]


Not yet available as coformulation

Concerns about monitoring renal function[4]

No guideline recommendation at this time

1. Walmsley S, et al. ICAAC 2012. Abstract H-556b. 2. Feinberg J, et al. ICAAC 2013. Abstract H-1464a. 3. Raffi F, et al. Lancet. 2013;381:735-743. 4. Dolutegravir [package insert].


Individualizing First-line Therapy: Specific CircumstancesCircumstance Agents

No genotype Use boosted PI

High HIV-1 RNA Caution with ABC, RPV

Renal disease Caution with TDF, ATV/RTV; monitoring complicated with COBI and DTG

Dyslipidemia RAL, DTG, RPV most lipid neutral

CV risk factors Possible association with ABC, ddI, LPV/RTV No data for DRV/RTV, INSTIs, MVC

Pregnancy Preferred: ZDV/3TC + NVP, LPV/RTV, or ATV/RTV EFV can be used after first 5-6 wks

Chronic HBV infection Preferred TDF + 3TC or FTC Alternative is entecavir

Decreased BMD Caution with TDF

Concerns about CNS effects Caution with EFV for at least first mo

Managing Patients Receiving First-line Therapy


What’s New in the Guidelines With Laboratory Tests Repeat HIV serology at entry into care if diagnosis not

confirmed

Obtain HCV serology at entry into care and when clinically indicated

A genotypic viral tropism test is now available, but the phenotypic test is preferred

At VF of an INSTI-based regimen, an integrase genotypic resistance assay should be obtained

DHHS Adult Guidelines. February 2013.

Adverse Events


Low Discontinuation for AEs in Clinical Trials With Preferred and Newer AgentsAgent Discontinuation Rate for AEs by Wk 48 in

Major Clinical Trials, %

EFV (ACTG 5202)[1] 9 (TDF/FTC arm)

ATV/RTV (CASTLE)[2] 2

DRV/RTV (ARTEMIS)[3] 3

RAL (STARTMRK)[4] 3

RPV (ECHO)[5] 2

EVG/COBI (GS102)[6] 4

DTG (SINGLE)[7] 2

1. Daar E, et al. Ann Intern Med. 2011;154:445-456. 2. Molina JM, et al. Lancet. 2008;372:646-655. 3. Ortiz R, et al. AIDS. 2008;22:1389-1397. 4. Lennox J, et al. Lancet. 2009;374:796-806. 5. Molina JM, et al. Lancet. 2011;378:238-246. 6. Sax P, et al. Lancet. 2012;379:2439-2448. 7. Walmsley S, et al. ICAAC 2012. Abstract H-556b.


Most Common Adverse Events Expected With Newer Drugs

Most Common AEs

RPV[1] Depressive disorders Headache Insomnia Rash

TDF/FTC/EVG/COBI[2] Nausea Diarrhea Abnormal dreams

DTG[3] Insomnia Headache

1. Rilpivirine [package insert]. 2. TDF/FTC/EVG/COBI [package insert]. 3. Dolutegravir [package insert].

Drug–Drug Interactions


Drug–Drug Interactions With First-line ART and Lipid-Lowering TherapyAntiretroviral Contraindicated Titrate Dose No Dose Adjustment

RPV[1] Atorvastatin

EVG/COBI/TDF/FTC[1]

LovastatinSimvastatin

AtorvastatinRosuvastatin

DTG[2]

ATV/RTV[1] LovastatinSimvastatin

AtorvastatinRosuvastatin

Pitavastatin

DRV/RTV[1] LovastatinSimvastatin

AtorvastatinPravastatin

Rosuvastatin

Pitavastatin

EFV[1] AtorvastatinSimvastatinPravastatin

Rosuvastatin

RAL[1]

1. DHHS Adult Guidelines. February 2013. 2. Dolutegravir [package insert].


Drug–Drug Interactions With OCPs

Antiretroviral Effect on OCP Dosing Recommendation

RPV[1,2] Ethinyl estradiol AUC 14%Norethindrone: no significant change

No dose adjustment

EVG/COBITDF/FTC[1,3]

Ethinyl estradiol AUC 25%Norgestimate

Weigh the risks and benefits of norgestimate and consider alternative contraceptive

DTG[4] No clinically relevant interaction No dose adjustment

ATV/RTV[1,2] Ethinyl estradiol AUC Norgestimate

OCP should contain ≥ 35 mcg ethinyl estradiol

DRV/RTV[1,2] Ethinyl estradiol AUC 44%Norethindrone AUC 14%

Additional methods of contraception recommended

EFV[1,2] No effect on ethinyl estradiolActive metabolites of norgestimate

A reliable method of barrier contraception must be used in addition to hormonal

contraceptives

RAL[1,2] No clinically relevant interaction No dose adjustment

1. DHHS Adult Guidelines. February 2013. 2. DHHS Perinatal Guidelines. July 2012. 3. TDF/FTC/EVG/COBI [package insert]. 4. Dolutegravir [package insert].


Drug–Drug Interactions With BOC and TVR

1. Rhee E, et al. CROI 2013. Abstract 537. 2. Rilpivirine [package insert]. 3. Custodio J, et al. ICAAC 2013. Abstract A-1576. 4. Dolutegravir [package insert]. 5. DHHS Adult Guidelines. February 2013.

Antiretroviral Interactions With Boceprevir Interactions With Telaprevir

RPV[1,2] No clinically relevant interactions No clinically relevant interactions

EVG/COBITDF/FTC[3]

No data No clinically relevant interactions

DTG[4] No clinically relevant interactions No clinically relevant interactions

ATV/RTV[5] Coadministration not recommended

Coadministration not recommended

DRV/RTV[5] Coadministration not recommended

Coadministration not recommended

EFV[5] Coadministration not recommended

Increase TVR dose to 1125 mg q8h

RAL[5] No clinically relevant interactions No clinically relevant interactions


Drug–Drug Interactions With Acid-Reducing Medications and Newer ARVsARV Antacids H2-Receptor

AntagonistsProton Pump

Inhibitors

RPV[1] Give antacids at least 2 hrs before or at

least 4 hrs after RPV

Give H2-receptor antagonists at least 12 hrs

before or at least 4 hrs after RPV

Contraindicated

EVG/COBITDF/FTC[1]

Separate EVG/COBI/ FTC/TDF and antacid

administration by > 2 hrs

No clinically relevant interactions


DTG[2] DTG should be given 2 hrs before or 6 hrs after

taking medications containing polyvalent

cations


1. DHHS Adult Guidelines. February 2013. 2. Dolutegravir [package insert].


Drug–Drug Interactions Between RTV-Boosted PIs and Steroid Preparations Steroid preparations should be given with caution with

boosted PIs, regardless of administration route

Coadministration can result in adrenal insufficiency, including Cushing’s syndrome; coadministration is not advised unless potential benefits outweigh the risks

DHHS Adult Guidelines. February 2013.

Managing ART in Pts Who Become Pregnant on Therapy


Changes in Perinatal Guidelines—2012

The Panel recommends that EFV be continued in pregnant women receiving EFV-based ART who present for antenatal care in the first trimester, provided the regimen is resulting in virologic suppression (CIII)

Pregnant women receiving and tolerating NVP-containing regimens who are virologically suppressed should continue the regimen, regardless of CD4+ cell count (AIII)

DHHS Perinatal Guidelines. July 2012.

Lipids


Lipid Comparisons in Clinical Trials

ARV Comparisons

RPV[1] vs EFV at Wk 48Smaller changes in TC, HDL-C, LDL-C, TG (all P < .0001)

COBI[2] vs RTV at Wk 48 when combined with ATVSimilar changes in lipids in all fractions

EVG/COBITDF/FTC[3-5]

vs EFV at Wk 48Smaller changes in TC (P < .001), HDL-C, LDL-C (both P = .001) Similar changes in TG between arms vs ATV/RTV at Wk 48Similar changes in TC, HDL-C, LDL-C Smaller change in TG (P = .006)

DTG[6] vs RAL at Wk 48Similar small changes in lipids in all fractionsvs EFV at Wk 48Smaller changes in TC, HDL-C, LDL-C

1. Cohen C, et al. AIDS. 2013;27:939-950. 2. Gallant J, et al. J Infect Dis. 2013;208:32-39. 3. Sax P, et al. Lancet. 2012;379:2439-2448. 4. DeJesus E, et al. Lancet. 2012;379: 2429-2438. 5. Sax P, et al. CROI 2012. Abstract 101. 6. Dolutegravir [package insert].


Lipid and Efficacy Data in Recent Switch Studies SPIRIT: Switch boosted PI to RPV vs remain on boosted

PI

– BL to Wk 48: improvement in mean fasting TC, LDL-C, TG, and TC:HDL-C ratio

– Switching noninferior to continuing boosted PI regimen at Wk 24

– Noninferiority maintained at Wk 48 but 5 additional cases of VF between Wks 24 and 48

Fisher M, et al. Glasgow 2012. Abstract P285.

Renal


EVG/COBI/TDF/FTC vs EFV or ATV/RTV: Creatinine Changes

Cobicistat is associated with reduced active secretion of creatinine in the renal tubules leading to initial rises in creatinine levels

Sax P, et al. Lancet. 2012;379:2439-2448. DeJesus E, et al. Lancet. 2012;379:2429-2438.

0.35

Ch

ang

e F

rom

BL

in

Ser

um

Cre

atin

ine

(mg

/dL

; IQ

R)

0.30

0.25

0

-0.05

-0.10

0.15

0.10

0.05

0.20

2 4 8 12 16 24 32 40 48Wks

EVG/COBI/TDF/FTCEFV/TDF/FTC

0.28

0.24

0.04

0

-0.04

0.16

0.12

0.08

0.20

Wks2 4 8 12 16 24 32 40 48

EVG/COBI/TDF/FTCATV/RTV + TDF/FTC

BLBL


SPRING-2: Changes in Serum Creatinine and Creatinine Clearance

DTG increases serum creatinine by the benign inhibition of the organic cation transporter 2, which is responsible for tubular secretion of creatinine[3]

1. Raffi F, et al. Lancet. 2013;381:735-743. 2 Raffi F, et al. AIDS 2012. Abstract THLBB04. 3. Koteff J, et al. Br J Clin Pharmacol. 2013;75:990-996.

Change in Serum Creatinine, Mean (± SD)[1]

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

of

Cre

ati

nin

e (

mg

/dL

)

0.28

0.22

0.17

0.11

0.06

0

2 4 8 12 16 24 32 40 48

Wk

Baseline (mg/mL): DTG 0.85 vs RAL 0.85

+0.14

+0.05

Change in CrCl, Mean (± SD)[2]

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

L/m

in)

10

0

10

-20

-30

BL 4 12 24 48

Wk

Baseline (mL/min): DTG 125 vs RAL 128

DTG 50 mg QD (n = 411)

0.06

RAL 400 mg BID (n = 411)


Special Considerations for Monitoring Renal Function Some drugs have an effect on creatinine including cimetidine,

cobicistat, trimethoprim, RPV, and DTG

– Expected minor increases in creatinine and decreases in estimated CrCl during treatment with these agents do not reflect changes in actual CrCl

Baseline CrCl < 70: do not use EVG/COBI/TDF/FTC

– Stop if estimated CrCl < 50 (cannot adjust dose)

Pts at risk of renal disease: monitor urine protein, glucose, serum phosphorus, and CrCl

– Confirmed rise in serum creatinine of > 0.4 mg/dL is considered significant


Summary

Several excellent options for first-line ART

– Safety and tolerability continues to improve

– Important differences in drug–drug interactions

Individualize selection and monitoring and plan for long-term success

Date post:	07-May-2015
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First and foremost choosing and using first line antiretroviral therapy.2013

Health & Medicine