This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice

related to any specific patient.

Mountain West AIDS Education and Training Center

Dolutegravir: Pros and Cons

(Are There Any Cons?)

Brian R. Wood, MD

Assistant Professor of Medicine, University of Washington

Medical Director, MW AETC ECHO

Last Updated: 10/20/16

Dolutegravir Pros and Cons

• Pros:

- High resistance barrier

- Small, once-daily tab

- Doesn’t require booster

- Few drug interactions

- Overall well tolerated

- Relatively lipid friendly

• Cons:

- Headache and insomnia

- Interactions with metformin,

cations, and other ARV’s

- Raises serum creatinine

- No TDF or TAF coformulation

DolutegravirRaltegravir

Dolutegravir Phase 3 Studies

• .

1) Raffi F, et al. Lancet Infect Dis. 2013;13(11):927-35.

2) Walmsley S et al. J Acquir Immune Defic Syndr. 2015:70(5):515-9.

3) Molina JM, et al. Lancet HIV. 2015;2(4):e127-36.

4) Cahn P, et al. Lancet 2013;382:700–8.

5) Castanga A, et al. J Infect Dis. 2014;210(3):354-62.

Study ARV History Comparison Results (HIV RNA <50)

1 SPRING-2 ARV-NaïveDolutegravir QD vs.

Raltegravir

• Non-inferior

(81% vs. 76%)

2 SINGLE ARV-NaïveDolutegravir QD vs.

Efavirenz

• Dolutegravir superior

(71% vs. 63%)

3 FLAMINGO ARV-NaïveDolutegravir QD vs.

Darunavir-RTV

• Dolutegravir superior

(80% vs. 68%)

4 SAILING>2-class

ARV resistance

Dolutegravir QD vs.

Raltegravir

• Dolutegravir superior

(71% vs. 64%)

5 VIKING-3Integrase

resistance

Single-arm,

Dolutegravir BID

• Virological suppression

(69%)

Review of Integrase and Dolutegravir

Resistance

Dolutegravir in Patients with Raltegravir Resistance

VIKING III: Results

Source: Dolutegravir Product Information.

64

80

56 54

18

0

20

40

60

80

100

All Patients N155Hwithout Q148

Y143C/H/Rwithout Q148

Q148H/R +G140A/S*

Q148H/R + ≥ 2 INSTI mutations

Pa

tie

nts

wit

h H

IV R

NA

< 5

0 c

op

ies

/ml (%

)

*without additional INSTI mutations

Sources:

Wainberg MA, et al. BMC Medicine. 2013;11:249.

Wainberg MA, et al. Can J Microbiol. 2016;62(5):375-82.

“Virological failure with resistance mutations in treatment-naïve patients treated with dolutegravir has not been reported.”

Dolutegravir Resistance

• Resistance mutations not yet reported in treatment-naïve

individuals (neither INSTI nor NRTI resistance)

• Reports of R263K & other mutations in treatment-

experienced patients and in vitro, yet dolutegravir generally

retains activity

Source: Wainberg MA, Han YS. Front Pharmacol. 2015;6:90.

Why are Dolutegravir Resistance Mutations So Rare

in Treatment-Naïve Persons?

• Reduced viral fitness & integrase enzyme activity

- No compensatory secondary mutations develop

- Mutations also delay development of NRTI/NNRTI mutations

- And common NRTI mutations prevent DTG mutations

• Drug has strong affinity/binding to integrase enzyme

• ?Resistance strains less likely to be archived

Source: Wainberg MA, et al. BMC Medicine. 2013;11:249-

Summary of Integrase Resistance Pathways

Source: Brenner BG, Wainberg MA. Virus Res. 2016. pii:S0168-1702(16)30283-0.

Raltegravir Elvitegravir Dolutegravir

Primary N155

Q148

Y143

N155

Q148

E92

T66

R263

G118

H51

E138

S153

N155

Secondary Common Common Rare

*RAL and ELV primary mutations lead to resistance

but also reduced viral fitness; secondary mutations

increase resistance further and rescue viral fitness,

but this doesn’t happen with DTG

Dolutegravir Tolerability, Side Effects, and

Drug Interactions

Dolutegravir Side EffectsIntolerance of DTG-Containing Regimens in Clinical Practice

• Two centers in the Netherlands

• Review of all ART-naïve and exp. patients starting DTG

• 556 patients included

• 85 (15.3%) discontinued the drug

• 75 (13.7%) discontinued due to intolerance

• Most frequent reason: insomnia/sleep disturbance

• Intolerance more frequent if combined with ABC (RR 1.92)

Source: de Boer M et al. AIDS. 2016. DOI:10.1097/QAD.0000000000001279.

STRIIVING Study

Switch to ABC/3TC/DTG from Other Standard ART

ABC/3TC/DTG

(n=275)

Other ART

(n=276)

Any adverse

event (AE)

180 (65%) 124 (45%)

Grade 3 or 4 AE 8 (3%) 5 (2%)

Discontinuation

due to AE

10 (4%) 0 (0%)

*However, reported treatment satisfaction scores

significantly higher in those who switched to

ABC/3TC/DTG

Source: Koteff J et al. EACS 2015, Barcelona, Spain.

Dolutegravir Increases Serum Creatinine by Benign Inhibition

of Tubular Secretion of Creatinine

Source: Koteff J, et al. Br J Clin Pharmacol. 2013:75:990-6.

Proximal Tubule Distal Tubule

Loop of Henle

Collecting

Tubule

Dolutegravir

Excretion

Inhibits tubular secretion of

creatinine via inhibition of OCT2

Organic Cation Transporter 2

(OCT2)

Bowman’s Capsule

Source: Dolutegravir Prescribing Information

Dolutegravir Drug Interactions and Dosing

Recommended Dolutegravir Dosing

Adult Population Recommended Dose

Treatment-naïve

or

Treatment-experienced INSTI-naïve

50 mg once daily

Coadministered with potent UGT1A/CYP3A inducer:

Efavirenz

Fosamprenavir/ritonavir

Tipranavir/ritonavir

Rifampin

50 mg twice daily

INSTI-experienced with certain INSTI mutations*

or

Clinically suspected INSTI resistance

50 mg twice daily

Poor virologic response associated with Q148 Substitution plus ≥ 2 more INSTI mutations

Source: Dolutegravir (Tivicay) Prescribing Information

Additional Dolutegravir Drug Interactions

Medication Interaction Recommendation

Etravirine Dolutegravir Avoid unless a boosted PI

is also in the regimen

Oxcarbazepine, phenytoin,

phenobarbital, carbamazepine,

St. John’s Wort

Dolutegravir Avoid

Cation-containing antacids or

laxatives (sucralfate, oral Fe, oral

Ca) or buffered medications

Dolutegravir Dolutegravir should be

administered 2 hours

before or 6 hours after

Metformin Metformin Close monitoring, consider

metformin dose adjustment

Dofelitide Dofelitide Avoid

Summary

• Dolutegravir is a revolutionary ARV and an excellent medication for many persons living with HIV, but not all

• Failure of raltegravir or elvitegravir can cause significant dolutegravir resistance, but failure of dolutegravir generally does not lead to resistance mutations

• 10-15% of individuals don’t tolerate dolutegravir due to insomnia, headache, or other side effects; intolerance may be more likely if combined with abacavir

• Remember the benign effects on serum creatinine and a few key drug-drug interactions

Question?

• What would be better than dolutegravir? What will be the

next revolutionary step?

- Cabotegravir?

- GS-9883 (Bictegravir)?

- MK-8591 (EFdA)?