Role of atazanavir in the treatment of HIV infection

Figures & data

Figure 1 Chemical structure of atazanavir sulfate.

Table 1 Different genotypic resistance scores for atazanavir (boosted or unboosted) in relation to clinical responses

Source	Protease inhibitor	Protease mutations	Clinical cut-off
Colonno et al^Citation2	Atazanavir	L10F/I/V, K20I/M/R, L24I, L33F/I/V, M36I/L/V, M46I/L, G48V, I54L/V, L63P, A71I/V/T, G73A/C/S/T, V82A/F/T/S, I84V, L90M, or the presence of I50L alone	<versus ≥4
ANRS 2004 www.sante.gouv.fr	Atazanavir–ritonavir	L10F/I/V, K20I/M/R, L24I, L33F/I/V, M36I/L/V, M46I/L, G48V, I54L/V, L63P, A71I/V/T, G73A/C/S/T, V82A/F/T/S, I84V, L90M, or the presence of I50L alone	<versus ≥6
ANRS 2005^Citation82	Atazanavir–ritonavir	L10F/I/V, G16E, L33F/I/V, M46I/L, D60E, I84V, I85V, L90M, or the presence of I50L alone	<versus ≥3
Pellegrin et al^Citation26	Atazanavir–ritonavir	L10F/I/V, K20I/M/R, L24I, M46I/L, I54L/V, Q58E, L63P, A71I/V/T, G73A/C/S/T, V77I, V82A/F/T/S, I84V, L90M, or the presence of I50L alone	<versus ≥5
Bertoli et al^Citation83	Atazanavir	L10C/I/V, V32I, E34Q, M46I/L, F53L, I54A/M/V, V82A/F/I/T, I84V, I15E/G/L/V, H69K/M/N/Q/R/T/Y, I72M/T/V	<versus ≥4
Bertoli et al^Citation83	Atazanavir–ritonavir	G16E, V32I, K20I/M/R/T/V, L33F/I/V, F53L/Y, I64L/M/V, A71I/T/V, I85V, I93L/M	<versus ≥3

Abbreviation: ANRS, agence nationale de recherche sur le sida et les hépatites Virales.

Table 2 Pharmacokinetic parameters at steady state after atazanavir 400 mg once daily and after atazanavir 300 mg with ritonavir 100 mg once daily with a light meal in HIV-infected patients

	ATV 400 mg	ATV/r 300/100 mg
Bioavailability (%)	68	Not available
Protein binding (%)	86	86
Distribution volume	Not available	Not available
Clh (L/h)	25.2	Not available
Clr of parent drug (%)	7	Not available
t1/2, mean ± SD (h)	6.5 ± 2.6	8.6 ± 2.3
Cmax, mean ± SD (ng/mL)	3152 ± 2231	5233 ± 3033
Tmax, median (h)	2	3
Cmin, mean ± SD (ng/mL)	273 ± 298	862 ± 838
AUC, mean ± SD (ng/mL/h)	22262 ± 20159	53761 ± 35294

Abbreviations: ATV, atazanavir; RTV, ritonavir; Clh, hepatic clearance; Clr, renal clearance; T_1/2, half-life; C_max, maximum concentration; T_max, time at C_max; C_min, minimum concentration; AUC, area under the curve.

Table 3 Main drug interactions with atazanavir 400 mg or atazanavir/ritonavir 300/100 mg/day

Family	Drug	Effect on concentration	Recommendation
Antiarrhythmics	amiodarone, bepridil, lidocaine, quinidine	↑ antiarrhythmic	Caution is warranted, TDM recommended.
Anticoagulants	warfarin	↑ warfarin	Monitoring of INR is recommended.
Anticonvulsants	carbamazepine, lamotrigine, phenobarbital, phenytoin	expected ↓ ATV	Use with caution.
Antidepressants	tricyclic antidepressants	↑ tricylcic antidepressants	Use with caution, TDM is recommended.
	trazodone	↑ trazodone	TDM is recommended and lower trazodone doses should be used
Antifungals	itraconazole, ketoconazole	↑ itraconazole, ketoconazole (ATV 400)	If ATV is used with RTV, itraconazole or ketoconazole doses of >200 mg/day should be used with caution.
Antihistamines	astemizole, terfenadine	no data available	ATV/r should not be used in combination with drugs that are substrates of the CYP3A4 and have narrow therapeutic windows, such as terfenadine and astemizole.
Antimicrobial agents	clarithromycin	↑ clarithromycin	Dose reductions by 50% should be considered.
		↓ 14-OH-clarithromycin	Combination with boosted ATV has not yet been studied.
		↑ ATV concentrations
Antineoplastics	irinotecan	↑ irinotecan	Contraindicated
Antimycobacterials	rifabutin	↑ rifabutin	Reduce rifabutin dose to 150 mg every other day or 3 times/week.
	rifampicin	severe ↓ ATV	Contraindicated.
Antiretroviral agents	NRTIs:
	didanosine	↓ ATV, ↓ didanosine	Didanosine should be administered (with food) 1 h before or 2 h after ATV/r intake.
	tenofovir	↓ ATV, ↑ tenofovir	Avoid combination of tenofovir with r unboosted ATV.
	NNRTIs:
	efavirenz	↓ ATV	The recommended dose in treatment-naïve patients is ATV/r 300/100 mg/day. No recommendation has been established in treatment-experienced patients.
	nevirapine	expected ↓ ATV	Co-administration is not recommended.
	etravirine	↑ etravirine, ↓ ATV	ATV should be boosted with r.
	IPs:
	indinavir		Contraindicated due to synergistic effect on hyperbilirubinemia.
	saquinavir (soft gelatin capsules)	↑ saquinavir	Appropiate recommendations for this combination have not been established. TDM is recommended.
	tipranavir	expected ↓ ATV	ATV and tipranavir should not be co-administered.
	INI:
	raltegravir	↑ raltegravir	The clinical relevance of these data is unknown. No changes in raltegravr dosign are recommended.
Benzodiazepines	midazolam, triazolam	↑ midazolam, triazolam	Contraindicated.
Calcium channel blockers	diltiazem	↑ diltiazem and desacetyl-diltiazem	Caution is warranted. 50% dose reduction of diltiazem should be considered.
	felodipine, nifedipine, nicardipine, verapamil	↑ felodipine, nifedipine, nicardipine, verapamil	Caution is warranted and ECG monitoring is recommended. Dose titration should be considered.
Corticosteroids	fluticasone	↑ fluticasone	Caution is warranted.
Ergot derivatives	dihydroergotamine, ergotamine, ergonovine, methylergonovine	↑ ergot derivatives	Contraindicated.
GI motility agent	cisapride	↑cisapride	Contraindicated.
Acid suppressive therapy	antiacids	↓ ATV	ATV should be adminsitered 2h befote or 1h alter intake of antiacids.
	H2 receptor antagonists	↓ ATV	H2 Receptor antagonist should not exceed a 40 mg dose equivalent of famotidine twice daily and ATV should be administered with r simultaneously, with and/or at least 10 hours after the dose of the H2-receptor antagonist.
	proton pump inhbitors	↓ ATV	ATV/r is recommended. Proton-pump inhibitor dose should not exceed a 20 mg dose/day, equivalent of omeprazole and must be taken approximately 12 hours prior to ATV/RTV in antiretroviral-naïve patients. Proton-pump inhibitors should not be used in treatment-experienced patients.
Herbal products	St. John’s wort	expected ↓ ATV	Contraindicated.
HMG-CoA reductase	lovastatin, simvastatin	↑ lovastatin, simvastatin	Contraindicated.
Inhbitors	atrovastatin, rosuvastatin	↑atorvastatin, rosuvastatin	Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring or consider other HMG-CoA reductase inhibitor such as pravastatin or fluvastatin.
Immuno-suppressants	cyclosporine A, sirolimus, tacrolimus	↑ immunosuppressants	TDM is recommended.
Neuroleptics	pimozide	↑ pimozide	Contraindicated.
Oral contraceptives	ethinyl estradiol, norethindrone	↓↑ oral contraceptives	Due to possible alteration of oral contraceptives concentrations, alternative/additional contraceptive measures should be used when co-administered with ATV or ATV/r.
PDE5 inhibitors	sildenafil, tadalafil, vardenafil	↑ sildenafil, tadalafil, vardenafil	Do not exceed 25 mg of sildenafil in 48 h, 10 mg of taldalafil in 72 hours or 2.5 mg of vardenafil in 72 h.

Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease Inhibitor; INI, integrase Inhibitor; ATV, atazanavir; RTV, ritonavir; TDM, therapeutic drug monitoring; INR, international normalized ratio; ECG, electrocardiogram.

Figure 2 Antiretrovirals, bilirubin and UGT inhibition.

Table 4 Main randomized studies with atazanavir in antiretroviral-naïve patients

Study	Phase	No	Backbone	Regimens	Follow-up (weeks)	% patients achieving plasma HIV-RNA <400 copies/mL (ITT)	% patients achieving plasma HIV-RNA <50 copies/mL (ITT)
AI424-007^Citation43	II	420	d4T + ddI	ATV 200 mg qd	48	61	28
				ATV 400 mg qd		64	36
				ATV 500 mg qd		59	42
				NFV 750 mg tid		56	39
AI424-008^Citation44	II/III	467	d4T + 3TC	ATV 400 mg qd	48	64	35
				ATV 600 mg qd		67	36
				NFV 1250 mg bid		53	34
AI424-034^Citation5	III	810	ZDV + 3TC	ATV 400 mg qd	48	70	32
				EFV 600 mg qd		64	37
CASTLE^Citation55	III	883	TDF + FTC	ATV/RTV 300/100 mg qd	48	86	78
				LPV/RTV 400/100 mg bid		82	76
AI424-089^Citation51	IV	200	3TC + d4T-XR	ATV 400 mg qd	96	85	70
				ATV/RTV 300/100 mg qd		86	75
ALERT^Citation54	IV	106	TDF + FTC	ATV/RTV 300/100 mg qd	48	87	83
				FPV/RTV 1400/100 mg qd		79	75

Abbreviations: ITT, intent-to-treat; VL, viral load; 3TC, lamivudine; d4T, stavudine; d4T-XR, extended-release stavudine; ddI, didanosine; TDF, tenofovir disoproxil fumarate; ATV, atazanavir; LPV, lopinavir/ritonavir; NFV, nelfinavir; FPV, fosamprenavir; RTV, ritonavir; EFV, efavirenz; ZDV, zidovudine; bid, twice daily; qd, once daily; tid, three times daily.

Table 5 Main randomized studies with atazanavir in antiretroviral-experienced patients with virologic failure

Study	Phase	n	Backbone	Regimens	Follow-up (weeks)	% patients achieving VL < 400 copies/mL (ITT)a	% patients achieving VL < 50 copies/mL (ITT)
AI424-009^Citation56	II	85	2 NRTIs based on phenotypic susceptibility data	ATV 400 mg qd + SQV 1200 mg qd	48	41	–
				ATV 600 mg qd + SQV 1200 mg qd		29	–
				SQV 400 mg bid + RTV 400 mg bid		35	–
AI424-043^Citation58	III	300	2 NRTIs based on phenotypic susceptibility data	ATV 400 mg qd	48	48	37
				LPV/RTV 400/100 mg bid		68	53
AI424-045^Citation59	III	358	TDF + 1 NRTI based on phenotypic susceptibility data	ATV/RTV 300/100 mg qd	96	44	33
				LPV/RTV 400/100 mg bid		46	36
				ATV 400 mg plus SQV 1200 mg qd	48	38	26

a Virological response in the AI424-009 study defined as > 1.0 log₁₀ decrease HIV-1 RNA or HIV-1 RNA < 400 copies/mL at week 48.

Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; ITT, intent-to-treat; VL, viral load; TDF, tenofovir disoproxil fumarate; SQV, saquinavir; LPV, lopinavir; RTV, ritonavir; ATV, atazanavir; bid, twice daily; qd, once daily.

Table 6 Main switch studies with atazanavir

Study	Phase	n	Backbone	Previous regimen	Intervention	Follow-up (weeks)	Main conclusion
AI424-044^Citation62	III	346	d4T + 3TC	ATV 400 mg qd	Continue on ATV (400 or 600 mg) or switch from NFV to ATV 400 mg qd	24	Maintenance of virologic suppression and significant improvement in lipid profile in patients switched to ATV
				ATV 600 mg qd
				NFV 1250 mg bid
AI424-067^Citation68	III	246	2 NRTI	PI with or without RTV	Immediate switch to ATV 400 mg qd or delayed switch after 24 weeks	48	Virologic rebounds >50 copies/mL, 15% in immediate switch and 10% in delayed switch group. Improvement in lipid profile in hyperlipidemic patients
AI424-097^Citation65	III	419	2 NRTI	PI with or without RTV	Continue existing PI or switch to ATV (400 mg qd) or to ATV/RTV (300/100 mg qd) if receiving TDF	48	Maintenance of virologic suppression and improvement in lipid profile in patients switched to ATV
SLOAT^Citation66	IV	189	2 NRTI	LPV/RTV	Continue on LPV/RTV or switch to ATV (400 mg qd) or to ATV/RTV (300/100 mg qd) if receiving TDF	24	Maintenance of virologic suppression and improvement in lipid profile in patients switched to ATV
ATAZIP^Citation67	IV	265	2 NRTI	LPV/RTV	Continue on LPV/RTV or switch to ATV ATV/RTV (300/100 mg qd)	48	Maintenance of virologic suppression and improvement in lipid profile in patients switched to ATV
ReAL^Citation73	IV	200	2 NRTI	PI/ritonavir	Continue existing PI or switch to ATV/RTV	48	Maintenance of virologic suppression and improvement in lipid profile but no significant change in body composition in patients switched to ATV
				(72% LPV/RTV)	(300/100 mg qd) in patients with lipohypertrophy

Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; ITT, intent-to-treat; VL, viral load; 3TC, lamivudine; d4T, stavudine; LPV, lopinavir; NFV, nelfinavir; RTV, ritonavir; ATV, atazanavir; bid, twice daily; qd, once daily.

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