Dolutegravir: A New HIV Integrase Inhibitor for the Treatment of HIV Infection

Blake Max; Sonia Vibhakar

Future Virology. 2014;9(11):967-978.

Abstract and Introduction

Abstract

Dolutegravir is a second-generation HIV integrase strand transfer inhibitor (INSTI) and the most recent antiretroviral approved for treatment of HIV-1 infection. Dolutegravir in combination with two nucleoside reverse transcriptase inhibitors is one of the preferred regimens recommended by the Department of Health and Human Services HIV treatment guidelines for treatment-naive adults and adolescents. This recommendation is based on clinical trial data where dolutegravir demonstrated superiority compared with guideline preferred regimens containing efavirenz and ritonavir-boosted darunavir and noninferiority compared with first-generation INSTI, raltegravir. Dolutegravir also demonstrated superiority when compared with raltegravir in treatment-experienced, integrase-naive patients and clinical efficacy in patients with resistance to first-generation INSTIs. Overall, dolutegravir has demonstrated excellent tolerability, limited drug interactions, minimal drug resistance and once-daily dosing for treatment-naive patients.

Introduction

For almost two decades antiretroviral therapy has decreased morbidity and mortality for HIV infected patients.^[1] Since the introduction of highly active antiretroviral therapy in 1996 medications to treat HIV have steadily improved. HIV clinicians now have at their disposal five distinct classes of antiretroviral medications, the most recent class that has had a major impact on the treatment of HIV infection are the HIV integrase strand transfer inhibitors (INSTIs). There are currently three US FDA approved INSTIs: raltegravir (Isentress®, Merck Sharp & Dohme Corp., NJ, USA), elvitegravir (available as a fixed dose combination tablet Stribild® [Stribild-Gilead Sciences, Inc., CA, USA] in the USA) and dolutegravir (Tivicay®, ViiV Healthcare, NC, USA). Dolutegravir, a second-generation INSTI, is the most recent FDA-approved antiretroviral that has demonstrated impressive antiviral efficacy based on randomized controlled trials compared with other first-line regimens recommended by the Department of Health and Human Services HIV treatment guidelines for adults and adolescents.^[2] Dolutegravir has excellent pharmacokinetic characteristics, is well tolerated, has few drug interactions, minimal drug resistance and can be dosed once or twice daily depending on prior HIV integrase resistance. In August 2013, dolutegravir was FDA approved for treatment of HIV-1 infected patients over the age of 12 years and weighing over 40 kg. This article reviews the pharmacology, pharmacokinetics, clinical efficacy, resistance, safety and drug interactions of dolutegravir.

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Table 1. Dolutegravir adverse effects.
Adverse Events	SPRING-1 (DTG 10, 25 or 50 mg vs EFV)	SINGLE (DTG + ABC/3TC vs EFV/TDF/FTC)	SPRING-2 (DTG vs RAL + either ABC/3TC or TDF/FTC	FLAMINGO (DTG + vs DRV/rtv + either ABC/3TC or TDF/FTC)
Insomnia	2% all grades	4% grade 2–4; 7% grade 1	<1% grade 2–4; 1% grade 1	Not reported
Headache	6% all grades	3% grade 2–4	<1% (12% all grades)	15% all grades
Nausea	12% all grades	2% grade 2–4	14% all grades	16% all grades
Diarrhea	8% all grades	5% grade 2–4	11% all grades	17% all grades
Rash	1%	<1%	<1%	Not reported
Liver Abnormality	Not reported	2% grade 2–4	3%	Not reported
Reference	[18,32]	[21]	[22,23]	[24]

3TC: Lamivudine; ABC: Abacavir; DRV: Darunavir; DTG: Dolutegravir; EFV: Efavirenz; FTC: Emtricitabine; rtv: Ritonavir; TDF: Tenofovir.

Table 2. Antiretroviral drug interactions with dolutegravir ^†.
Drug	Change in drug or DTG concentration	Dose modification	Ref.
NRTIs	No drug interactions with DTG and NRTIs	No dose modification needed	[10]
NNRTIs
Efavirenz	DTG AUC ↓57%, C_max ↓39% and C_min ↓75%	DTG must be given 50 mg b.i.d.	[37]
Nevirapine	No Data	Should be avoided due to insufficient data however lower DTG levels would be suspected	[10]
RPV	DTG AUC ↑12%, C_max ↑13% and C_min ↑22% RPV C_min ↑21%	No dose modification needed	[33]
ETR	DTG AUC ↓70%, C_max ↓52% and C_min ↓88%	Should not be coadministered together EXCEPT if given with ATV/ritonavir, DRV/ritonavir or LPV/ritonavir	[34]
	ETR + LPV/ritonavir + DTG: no effect on DTG AUC or C_max and C_min ↑28%
	ETR + DRV/ritonavir + DTG: AUC ↓25%, C_max ↓12% and C_min ↓37%	When given with a ritonavir-boosted PI and ETR, the effect on DTG is reduced and the changes are not clinically significant
Protease inhibitors
ATV	ATV/ritonavir ↑AUC of DTG 62%, ↑C_max 34% and↑C_min 121%	Coadministration was well tolerated and no dose modification is needed	[35]
	ATV 400 mg ↑AUC of DTG 91%, ↑C_max 50% and ↑C_min 180%	Increased incidence of scleral icterus seen with atazanavir
DRV	DTG 30 mg daily studied with DRV/ritonavir 600/100 mg: DTG AUC ↓22%, C_max ↓11% and C_min ↓38%	Not clinically significant and no dose modification needed	[36]
fAMP	fAMP/ritonavir 700/100 mg with DTG 50 mg daily: AUC ↓35%, C_max ↓24% and C_min ↓49%	DTG is recommended to be dosed at 50 mg twice daily (US prescribing information) European recommendation is no dose adjustment necessary in integrase naive patients and an alternative should be used in integrase experienced patients	[38]
Lopinavir/ritonavir	No effect on DTG PK	No dose modification needed	[36]
Tipranavir/ritonavir	DTG AUC ↓59%, C_max ↓46% and C_min ↓76% via induction of UGT1A1 and CYP3A4	Increase DTG dose to 50 mg twice daily	[37]
Entry inhibitors
Enfuvirtide	No interaction suspected; clinical data available from VIKING study	No dose modification needed	[10]
Maraviroc	No interaction suspected; clinical data available from VIKING study	No dose modification needed	[10]

↓: Decrease; ↑: Increase; AUC: Area under the curve; ATV: Atazanavir; b.i.d.: Twice daily; C_max: Maximum plasma concentration; C_min: Minimum concentration needed to inhibit 50% of viral growth for wild-type HIV virus; DTG: Dolutegravir; DRV: Darunavir; ETR: Etravirine; fAMP: Fosamprenavir; LPV: Lopinavir; NRTI: Nucleoside reverse transcriptase inhibitor; PI: Protease inhibitor; PK: Pharmacokinetics; RPV: Rilpivirine.
Data taken from [10,33–38].