Long-Term Efficacy, Tolerability, and Renal Safety of Atazanavir/Ritonavir-based Antiretroviral Therapy in a Cohort of Treatment-Naïve Patients with HIV-1 Infection: the REMAIN Study

Figures & data

Figure 1 Patient disposition from enrollment to eligibility. ARV, antiretroviral; ATV/r, ritonavir-boosted atazanavir; NRTI, nucleos(t)ide reverse transcriptase inhibitors.

Table 1 Demographic and baseline characteristics

	Germany (N = 167)	Portugal (N = 185)	Spain (N = 165)	Overall (N = 517)
Age at ATV/r initiation, median (IQR), years	41 (32, 48)	41 (35, 51)	39 (33, 45)	40 (33, 48)
Male gender, n (%)	136 (81.4)	128 (69.2)	129 (78.2)	393 (76.0)
Race, n (%)
White	149 (89.2)	166 (89.7)	147 (89.1)	462 (89.4)
Black or African-American	11 (6.6)	19 (10.3)	8 (4.8)	38 (7.4)
Other	7 (4.2)	0	10 (6.1)	17 (3.3)
Route of transmission, n/N# (%)
Heterosexual	13/126 (10.3)	80/179 (44.7)	48/146 (32.9)	141/451 (31.3)
Men who have sex with men	91/126 (72.2)	27/179 (15.1)	62/146 (42.5)	180/451 (39.9)
Sexual not categorized	12/126 (9.5)	33/179 (18.4)	7/146 (4.8)	52/451 (11.5)
Intravenous drug use	9/126 (7.1)	39/179 (21.8)	28/146 (19.2)	76/451 (16.9)
Other	1/126 (0.8)	0	1/146 (0.7)	2/451 (0.4)
CDC Class C AIDS, n/N# (%)	21/162 (13.0)	47/185 (25.4)	26/154 (16.9)	94/501 (18.8)
Hepatitis C co-infection, n/N# (%)	19/152 (12.5)	42/185 (22.7)	31/158 (19.6)	92/495 (18.6)
HIV-1 RNA ≥100,000 copies/mL, n/N# (%)	67/155 (43.2)	81/181 (44.8)	65/157 (41.4)	213/493 (43.2)
CD4 count, n/N# (%)
<200 cells/mm^3	56/156 (35.9)	84/179 (46.9)	47/155 (30.3)	187/490 (38.2)
<50 cells/mm^3	10/156 (6.4)	27/179 (15.1)	14/155 (9.0)	51/490 (10.4)
Time of ATV/r exposure, median (IQR), months	44.0 (27.4, 54.1)	40.8 (20.6, 51.4)	39.5 (15.8, 49.1)	41.0 (21.0, 51.4)
Backbone antiretroviral therapy, n (%)
Fixed-dose combinations
TDF/FTC (Truvada^®)	152 (91.0)	147 (79.5)	124 (75.2)	423 (81.8)
ABC/3TC	11 (6.6)	23 (12.4)	14 (8.5)	48 (9.3)
ZDV/3TC	2 (1.2)	0 (0)	3 (1.8)	5 (1.0)
Other antiretrovirals
Abacavir	0 (0)	2 (1.1)	4 (2.4)	6 (1.2)
Emtricitabine	1 (0.6)	13 (7.0)	18 (10.9)	32 (6.2)
Lamivudine	1 (0.6)	1 (0.5)	5 (3.0)	7 (1.4)
Nevirapine	1 (0.6)	1 (0.5)	0 (0)	2 (0.4)
Ritonavir	20 (12.0)	1 (0.5)	0 (0)	21 (4.1)
Tenofovir	1 (0.6)	13 (7.0)	20 (12.1)	34 (6.6)
Zidovudine	1 (0.6)	1 (0.5)	1 (0.6)	3 (0.6)
Baseline eGFR,^a median (IQR), mL/min	102.1 (87.5, 116.4)	105.1 (92.7, 125.4)	99.8 (85.1, 119.8)	102.1 (88.9, 120.6)

Note: N = total number of patients; n = number of patients with characteristic; N# = total number of patients with available data for each characteristic.

^a Available in 455 patients – eGFR calculated using Modification of Diet in Renal Disease formula. ABC/3TC, abacavir/lamivudine; ATV/r, ritonavir-boosted atazanavir; CDC, Centers for Disease Control and Prevention; eGFR, estimated glomerular filtration rate; IQR, interquartile range; TDF/FTC, tenofovir disoproxil fumarate/emtricitabine; ZDV/3TC, zidovudine/lamivudine.

Figure 2 Time to discontinuation of treatment (A) and time to virologic failure using ≥ 50 copies/mL cut-off (B) and using ≥ 500 copies/mL cut-off (C). ATV/r, ritonavir-boosted atazanavir; BL, baseline; CI, confidence interval.

Table 2 Univariate and multivariate Cox proportional hazards models for time to discontinuation of an ATV/r-based regimen

Univariate analysis
Baseline covariate	Continuous or covariate subcategories	HR (95% CI)^a	P-value (HR = 1)^b	P-value Type 3 Test (β = 0)^c
Gender	Males relative to females	0.83 (0.62, 1.12)	0.22847	0.22847
HIV-1 RNA level	≥100,000 relative to <100,000 copies/mL	1.21 (0.92, 1.58)	0.17039	0.17039
Hepatitis B virus co-infection	Present relative to not present	0.73 (0.36, 1.49)	0.38843	0.44477
	Unknown relative to not present	0.77 (0.47, 1.29)	0.32629
Hepatitis C virus co-infection	Present relative to not present	0.99 (0.71, 1.40)	0.96565	0.77344
	Unknown relative to not present	0.77 (0.38, 1.57)	0.47372
Country	Germany relative to Spain	0.65 (0.46, 0.90)	0.00913	0.03113
	Portugal relative to Spain	0.79 (0.58, 1.07)	0.12777
Age at ATV/r initiation (years)	<50 relative to ≥50	0.86 (0.63, 1.16)	0.32175	0.32175
	Continuous	1.01 (0.99, 1.02)	0.30526	0.30526
Disease duration^d (years)	Continuous	1.01 (0.97, 1.04)	0.73004	0.73004
Mode of HIV acquisition	IVDU relative to other	1.13 (0.78, 1.64)	0.52113	0.53152
	Unknown relative to other	1.22 (0.83, 1.78)	0.3074
CD4 count at baseline	<200 copies/mm^3 relative to ≥350 copies/mm^3	1.18 (0.83, 1.69)	0.35261	0.26431
	200–350 copies/mm^3 relative to ≥350 copies/mm^3	0.92 (0.64, 1.32)	0.64589
	Continuous	1.00 (1.00, 1.00)	0.19211	0.19211
Opportunistic infection history	Present relative to not present	1.38 (1.01, 1.89)	0.04275	0.01503
	Unknown relative to not present	2.29 (1.12, 4.65)	0.02273
Multivariate analysis^e
Baseline covariate	Continuous or covariate subcategories	Adjusted HR (95% CI)^f	P-value (adjusted HR = 1)^g	P-value Type 3 Test (β = 0)^c
Gender	Males relative to females	0.77 (0.56, 1.06)	0.112	0.112
HIV-1 RNA level	≥100,000 relative to <100,000 copies/mL	1.26 (0.96, 1.66)	0.101	0.101
Hepatitis B virus co-infection	Present relative to not present	0.90 (0.44, 1.84)	0.771	0.949
	Unknown relative to not present	0.95 (0.47, 1.90)	0.881
Hepatitis C virus co-infection	Present relative to not present	1.05 (0.74, 1.49)	0.796	0.611
	Unknown relative to not present	0.61 (0.22, 1.71)	0.343
Country	Germany relative to Spain	0.67 (0.47, 0.95)	0.024	0.049
	Portugal relative to Spain	0.74 (0.54, 1.03)	0.071

^a Crude (unadjusted) HR of time to discontinuation of ATV/r-based regimen (in months).

^b P-value tests HR = 1;

^c Tests the overall effect of the factor (global null hypothesis: β = 0). Factors with a type 3 test p-value < 0.2 were eligible for entering for inclusion in the starting multivariate model provided excessive collinearity was not present.

^d Since ATV/r initiation.

^e Gender, category of viral load at baseline, and co-infection with hepatitis B or C virus at baseline were forced into all models. Other cofactors/covariates were selected if they were significant at level 0.2 in the univariate Cox model (type 3 test), displayed limited collinearity, and were retained following a forward selection process. The number of patients able to be included in the final model was 493/517 (95.4%).

^f Covariate adjusted HR of time to discontinuation of ATV/r-based regimen (in months).

^g P-value tests adjusted HR = 1.

ATV/r, ritonavir-boosted atazanavir; CI, confidence interval; HR, hazard ratio.

Table 3 Reasons given by the investigator for discontinuation

	Germany (N = 167)	Portugal (N = 185)	Spain (N = 165)	Overall (N = 517)
ATV/r discontinuation, n (%)	62 (37.1)	78 (42.2)	83 (50.3)	223 (43.1)
Reasons for discontinuation,^a n (%)
Virologic failure^b	5 (3.0)	19 (10.3)	11 (6.7)	35 (6.8)
Adverse event	34 (20.4)	17 (9.2)	31 (18.8)	82 (15.9)
Nausea	2 (1.2)	1 (0.5)	2 (1.2)	5 (1.0)
Vomiting	1 (0.6)	3 (1.6)	3 (1.8)	7 (1.4)
Renal failure	3 (1.8)	0	2 (1.2)	5 (1.0)
Hyperbilirubinemia-related^c	19 (11.4)	10 (5.4)	17 (10.3)	46 (8.9)
Poor/non-compliance	4 (2.4)	9 (4.9)	2 (1.2)	15 (2.9)
Concomitant disease	1 (0.6)	0	0	1 (0.2)
Patient request	8 (4.8)	2 (1.1)	3 (1.8)	13 (2.5)
Drug interaction	2 (1.2)	3 (1.6)	3 (1.8)	8 (1.5)
Medical decision/regimen simplification	7 (4.2)	21 (11.4)	21 (12.7)	49 (9.5)
Consent unavailable for 1-year extension	2 (1.2)	11 (5.9)	14 (8.5)	27 (5.2)
Other	1 (0.6)	3 (1.6)	0	4 (0.8)
Unknown	0	1 (0.5)	1 (0.6)	2 (0.4)

^a Patients could discontinue ATV treatment for more than one reason.

^b Virologic failure reported by the investigator as reason for discontinuation.

^c The number of patients with at least one hyperbilirubinemia-related discontinuation was calculated: four patients (three from Germany and one from Portugal) each had two hyperbilirubinemia-related reasons recorded; therefore, four of these reasons were excluded from this calculation.

Figure 3 Mixed-model repeated measures estimates of mean CD4 count over time. ATV/r, ritonavir-boosted atazanavir; CI, confidence interval.

Table 4 Selected treatment-emergent clinical and laboratory AEs (regardless of causality): incidence in the overall population of eligible patients (N = 517)

Total and selected clinical AEs (any grade)	n (%)
Patients with any AE	251 (48.5)
Diarrhea	10 (1.9)
Nausea	10 (1.9)
Vomiting	13 (2.5)
Hyperbilirubinemia	152 (29.4)
Jaundice	22 (4.3)
Ocular icterus	10 (1.9)
Renal and urinary disorders	17 (3.3)
Chromaturia	1 (0.2)
Dysuria	1 (0.2)
Nephrolithiasis	8 (1.5)
Pollakiuria	1 (0.2)
Renal colic	2 (0.4)
Renal failure	5 (1.0)
Laboratory AEs (Grade 3–4)	n^a / N^b (%)
ALT (> 5.1 × ULN)	18/504 (3.6)
AST (> 5.1 × ULN)	5/504 (1.0)
Total cholesterol (≥ 300 mg/dL)	14/496 (2.8)
Triglycerides (≥ 751 mg/dL)	8/497 (1.6)
LDL-cholesterol (≥ 190 mg/dL)	28/434 (6.5)
Total bilirubin (> 2.5 × ULN)	188/497 (37.8)
Creatinine (> 2 × ULN)	3/499 (0.6)

n^a = number of patients with at least one laboratory value above thresholds whilst on treatment. N^b = patients with available laboratory parameter values while on treatment. For laboratory abnormalities, the highest post-baseline value was considered. Clinical AEs reported by investigator were coded and grouped using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). Patients with more than one AE with the same preferred term were counted once for that term. Toxicity grades were defined according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDL, low-density lipoprotein; ULN, upper limit of normal.

Table 5 Patients discontinued due to hyperbilirubinemia: reasons given by the investigator versus confirmed grading from bilirubin measurement

Data: n (% of 46) [% of 517]	Reason given for discontinuation by the investigator
Confirmed Grade	Raised blood bilirubin^a	Jaundice	Ocular icterus	Yellow skin	Total
Grade 1–2 hyperbilirubinemia	6 (13) [1.2]	3 (6.5) [0.6]	4 (8.7) [0.8]	(0) [0]	13 (28.3) [2.5]
Grade 3–4 hyperbilirubinemia	12 (26.1) [2.3]	6 (13) [1.2]	3 (6.5) [0.6]	(0) [0]	21 (45.7) [4.1]
Measurement unavailable	3 (6.5) [0.6]	7 (15.2) [1.4]	1 (2.2) [0.2]	1 (2.2) [0.2]	12 (26.1) [2.3]
Total	21 (45.7) [4.1]	16 (34.8) [3.1]	8 (17.4) [1.5]	1 (2.2) [0.2]	46 (100) [8.9]

^a Terms recorded by the investigator for this category included, ‘hyperbilirubinemia’, ‘blood bilirubin abnormal’, and ‘blood bilirubin increased’.

Figure 4 Mixed-model repeated measures estimates of mean estimated glomerular filtration rate (eGFR) over time. ATV/r, ritonavir-boosted atazanavir; CI, confidence interval.