Table 2.

Summary of Integrase Strand Transfer Inhibitor pharmacokinetic studies in participants with hepatic impairment or severe renal impairment (estimated creatinine clearance <30 mL/min)

Antiretroviral	Study design	Participants	Cmax Ratio Impairment vs. Healthy	Cmin Ratio Impairment vs. Healthy	AUC∞ Ratio Impairment vs. Healthy
Moderate hepatic impairment
Bictegravira[55]	Parallel-group, single dose, PK evaluation over 144 hours HIV seronegative volunteers	Moderate hepatic impairment:b n=10 Matched, healthy volunteers: n=10	0.64 (0.50, 0.81)	na	0.59 (0.41, 0.84)
Cabotegravira[56]	Parallel-group, single dose, PK evaluation over 168 hours HIV seronegative volunteers	Moderate hepatic impairment:b n=8 Matched, healthy volunteers: n=8	0.69 (0.51, 0.93)	0.73 (0.53, 1.02)	0.73 (0.50, 1.06)
Dolutegravira[57]	Parallel-group, single dose, PK evaluation over 72 hours HIV seronegative volunteers	Moderate hepatic impairment:b n=8 Matched, healthy volunteers: n=8	1.02 (0.75, 1.37)	na	1.05 (0.75, 1.49)
Elvitegravirc[59]	Parallel-group, multiple dose, PK evaluation over 96 hours HIV seronegative volunteers EVG given as EVG/c/TDF/FTC given daily for 10 days	Moderate hepatic impairment:b n=10 Matched, healthy volunteers: n=10	EVG: 1.41 (1.09, 1.83) COBI: 0.861 (0.654, 1.13)	EVG: 1.80 (1.11, 2.91) COBI: 2.08 (1.17, 3.68)	EVG: 1.35 (1.03, 1.77) COBI: 0.997 (0.76, 1.31)
Raltegravirc [61]	Parallel-group, single dose, PK evaluation over 96 hours HIV seronegative volunteers	Moderate hepatic impairment:b n=8 Matched, healthy volunteers: n=8	0.63 (0.23, 1.70)	1.26 (0.65, 2.43)	0.86 (0.41, 1.77)
Raltegravird [62]	Parallel-group, steady state, Ctrough evaluation HIV-positive participants with or without HCV co-infection	HIV/HCV co-infection:e n=13 HIV monoinfection: n=16	na	1.16 (0.56, 1.39)	na
Raltegravirc [63]	Parallel-group, steady state, PK evaluation over a 12-hour dosing interval HIV-positive participants with HCV co-infection	HIV/HCV co-infection with advanced cirrhosis:f n=5 HIV/HCV co-infection without cirrhosis:g n=5	1.15 (0.55, 2.43)	6.58 (2.92, 14.85)	1.72 (1.02, 2.92)
Severe renal impairment
Bictegravira[55]	Parallel-group, single dose, PK evaluation over 144 hours HIV-seronegative volunteers	CLCR 15–29ml/min: n=10 Matched, healthy volunteers: n=8	0.80 (0.60, 1.08)	na	0.73 (0.49, 1.08)
Cabotegravira [65]	Parallel-group, single dose, PK evaluation over 168 hours HIV-seronegative volunteers	CLCR <30ml/min: n=8 Matched, healthy volunteers: n=8	1.01 (0.87, 1.17)	1.02 (0.87–1.20)	0.97 (0.84, 1.14)
Dolutegravira [66]	Parallel-group, single dose, PK evaluation over 72 hours HIV-seronegative volunteers	CLCrI <30ml/min: n=8 Matched, healthy volunteers: n=8	0.774 (0.532, 1.13)	0.566 (0.352, 0.908)	0.6 (0.37, 0.975)
Elvitegravirc [67]	Parallel-group, multiple dose, PK evaluation over 24 hours HIV-seronegative volunteers EVG given as EVG/c given daily for 7 days	CLCr <30ml/min: n=12 Matched, healthy volunteers: n=12	0.67 (0.55, 0.83)	0.76 (0.63, 0.91)	0.69 (0.52, 0.92)
Raltegravirc [61]	Parallel-group, single dose, PK evaluation over 96 hours HIV-seronegative volunteers	CLCr <30ml/min: n=10 Matched, healthy volunteers: n=10	0.68 (0.35, 1.32)	1.28 (0.79, 2,06)	0.85 (0.49, 1.49)

Abbreviations: ART, antiretroviral therapy; AUC_∞, area under the concentration time curve; C_max maximum concentration observed; C_min minimum concentration observed; COBI, cobicistat; CL_CR, estimated creatinine clearance; DTG, dolutegravir; EVG, elvitegravir; EVG/c/TDF/FTC, elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine co-formulated tablet; HCV, hepatitis C virus; HIV, human immunodeficiency virus; na, not available.

^aData presented as geometric least squares mean ratio (90% confidence interval).

^bModerate hepatic impairment was defined as Child-Pugh score 7–9.

^cData presented as geometric mean ratio (90% confidence interval).

^dData presented as geometric mean ratio (95% confidence interval).

^ePatients with mild or moderate hepatic impairment, all without cirrhosis.

^fAdvanced cirrhosis based on biopsy, Metavir score F4.

^gNon-cirrhosis based on biopsy, Metavir score F0–F1.