Influence of SULT1A1*2 Polymorphism on Plasma Efavirenz Concentration in Thai HIV-1 Patients

Figures & data

Table 1 Patient Demographics (n=149)

Data Characteristics, (Number of Patients) at Baseline	Value
HIV-1 positive	100%
Age, mean±SD (range; min-max), years	37.4±8.54 (19–59)
Gender, number (%)
-Males	116 (77.9%)
-Females	33 (22.1%)
Body weight, mean±SD (min-max), Kg	54.6±9.5 (31–86)
CD4 cell count, median (IQR), cells/mm3	42 (17–109)
Plasma HIV-1 RNA, median (IQR), Log copies/mL	5.8 (5.4–6.2)
Hemoglobin, mean±SD, g/dL	10.8±1.8 (6.5–15.5)
Blood Urea Nitrogen, median (IQR), mg/dL	10 (7–11)
Serum creatinine, mean±SD (min-max), mg/dL	0.7±0.2 (0.3–1.3)
Direct bilirubin, median (IQR), mg/dL	0.2 (0.1–0.4)
Total bilirubin, median (IQR), mg/dL	0.5 (0.3–0.7)
Alkaline phosphatase, median (IQR), mg/dL	105 (74–167)
Aspartate aminotransferase, median (IQR), U/L	37 (27–52)
Alanine aminotransferase, median (IQR), U/L	31 (19–46)

Table 2 SULT1A1 and UGT2B17 Gene Copy Number (CN) Distribution Among Different Ethnic Populations

SULT1A1 gene copy number	Present study (n=149)	Charoenchokthavee et al 2016^Citation31	Hebbring et al 2007^Citation32	Gjerde et al 2008^Citation33	Gaedigk et al 2012^Citation30	Tremmel et al 2017^Citation34	Almal et al 2017^Citation35	Yu et al 2013^Citation36	Li et al 2010^Citation37
Ethnicity	Thai	Thai	Caucasian-American	European-Caucasian	Caucasian	European-Caucasian	Indian	Japanese	Chinese
1	3.4%	0%	4.7%	5.3%	4.3%	3.3%	3.8%	0%	1.7%
2	48.3%	97.1%	69.6%	64.9%	47.2%	60.3%	64.9%	65%	75.7%
3	29.5%	2.9%	21%	21.8%	35.4%	29.8%	21.7%	25.8%	NA
4	11.4%	0%	3.6%	6%	9.3%	NA	5.1%	NA	NA
5	4.7%	0%	NA	2%	3.5%	NA	NA	NA	NA
6	2.7%	0%	NA	0%	0.3%	NA	NA	NA	NA
>2	48.3%	2.9%	25.7%	29.8%	48.5%	36.4%	31.3%	35%	22.6%
≥4	18.8%	NA	4.7%	8%	13.1%	6.6%	CN>4 (4.5%)	9.2%	22.6%
UGT2B17 gene copy number		Angstadt et al 2013^Citation41	Chew et al 2011^Citation42	Haas et al 2014^Citation24	Gaedigk et al 2012^Citation30	Uddin et al 2013^Citation43	Song et al 2017^Citation66	Mafune et al 2015^Citation40	Yang et al 2008^Citation39
Ethnicity		American	Caucasian	Hispanic&Non-Hispanic-American	Caucasian	European-Caucasian	Chinese	Japanese	Chinese
0	56.4%	14%	12%	6%	11.6%	13%	NA	80%	76.8%
1	34.2%	47.8%	45.5%	43%	46.7%	51%	CN<2 (73%)	19%	21.6%
2	9.4%	38.2%	42.5%	49%	40.6%	35%	27%	1%	1.6%
>2	0%	0%	0%	1%	1.2%	0%	0%	0%	0%

Abbreviation: NA, not applicable.

Table 3 Relationship Between Genetic Variation in Drug-Metabolizing Enzyme and Transporter Genes and Plasma Efavirenz Concentrations (N=149)

Gene	N=149 (%)	EFV Plasma Concentration (mg/L), Median (IQR), Week 12	EFV Plasma Concentration (mg/L), Median (IQR), Week 24	P value^┼
ABCA1 c.4760A>G (rs2230808)
A/A	32 (21.5)	2.07 (1.29–3.46)	2.62 (1.31–3.81)	0.601
A/G	69 (46.3)	2.23 (1.34–3.53)	2.33 (1.60–4.21)	0.644
G/G	48 (32.2)	2.94 (1.78–4.59)	2.22 (1.54–3.10)	0.056
P-value		0.103	0.775
ABCC2 g.68231A>G (rs3740065)
A/A	63 (42.3)	2.43 (1.57–4.10)	2.22 (1.54–3.41)	0.059
A/G	86 (57.7)	2.40 (1.36–4.21)	2.38 (1.55–4.01)	0.728
P-value		0.476	0.596
ABCC2 c.-24C>T (rs717620)
C/C	88 (59.1)	2.43 (1.52–4.26)	2.50 (1.56–3.84)	0.943
C/T	56 (37.6)	2.23 (1.41–4.14)	2.22 (1.44–4.04)	0.118
T/T	5 (3.3)	2.29 (1.57–2.38)	2.13 (1.58–3.10)	0.225
P-value		0.688	0.721
ABCC4 c.3348A>G (rs1751034)
A/A	97 (65.1)	2.41 (1.57–4.99)	2.36 (1.55–3.67)	0.526
A/G	45 (30.2)	2.29 (1.43–5.02)	2.33 (1.56–4.24)	0.343
G/G	7 (4.7)	2.43 (1.03–2.73)	1.81 (1.07–2.46)	0.735
P-value		0.516	0.322
SULT1A1 c.638G>A (rs1042028)
G/G	123 (82.6)	2.39 (1.41–4.54)	2.33 (1.57–4.21)	0.629
G/A	26 (17.4)	2.41 (1.48–3.22)	2.18 (1.44–2.60)	0.109
P-value		0.638	0.048^ǂ
SULT1A1 copy number (CN)
1	5 (3.4)	2.43 (1.34–4.97)	2.46 (2.22–2.55)	0.500
2	72 (48.3)	2.78 (1.64–4.24)	2.32 (1.61–4.01)	0.143
3	44 (29.5)	2.06 (1.26–2.82)	2.22 (1.47–4.02)	0.524
4	17 (11.4)	2.02 (1.43–3.89)	2.30 (1.47–3.00)	0.756
5	7 (4.7)	2.77 (1.33–5.84)	2.72 (1.09–5.58)	0.398
6	4 (2.7)	3.95 (2.45–5.32)	2.10 (1.60–2.98)	0.068
>2	72 (48.3)	2.07 (1.39–3.22)	2.30 (1.52–3.51)	0.860
P-value		0.194	0.958
UGT2B7 c.-161C>T (rs7668258)
C/C	88 (59.1)	2.20 (1.45–3.94)	2.22 (1.57–3.50)	0.126
C/T	52 (34.9)	2.78 (1.56–4.78)	2.33 (1.52–4.24)	0.536
T/T	9 (6)	2.15 (1.37–2.55)	2.85 (1.47–3.87)	0.012^ǂ
P-value		0.269	0.776
UGT2B7 c.211G>T (rs12233719)
G/G	124 (83.2)	2.43 (1.52–4.12)	2.30 (1.54–3.59)	0.137
G/T	24 (16.1)	1.74 (1.36–3.41)	2.46 (1.95–4.19)	0.317
T/T	1 (0.7)	4.63 (4.63–4.63)	4.17 (4.17–4.17)	0.317
P-value		0.353	0.462
UGT2B7 c.372A>G (rs28365063)
A/A	80 (53.7)	2.57 (1.39–4.16)	2.22 (1.42–3.50)	0.094
A/G	59 (39.6)	2.41 (1.69–3.51)	2.55 (1.84–4.42)	0.786
G/G	10 (6.7)	1.58 (1.30–4.63)	2.22 (1.36–4.17)	0.876
P-value		0.720	0.271
UGT2B17 copy number
0	84 (56.4)	2.42 (1.46–3.92)	2.37 (1.54–3.64)	0.450
1	51 (34.2)	2.38 (1.48–4.10)	2.22 (1.52–3.59)	0.297
2	14 (9.4)	2.84 (1.24–5.42)	2.63 (2.05–5.52)	0.875
0–1	135 (90.6)	2.41 (1.48–3.99)	2.30 (1.53–3.62)	0.216
P-value		0.969	0.300

Notes: ^┼Wilcoxon matched pairs test (comparing two groups); ^ǂSignificance (P<0.05); A post-hoc analysis of plasma EFV concentrations and SULT1A1 copy number at week 12 was as follows: CN=2 vs CN ≥3 (P = 0.046), CN=2 vs CN=3 (p=0.019), CN=2 vs CN=3+4 (P = 0.015).

Table 4 Univariate and Multivariate Analyses of Genetic and Non-Genetic Factors Associated with Plasma Efavirenz Concentrations at Week 12 and 24 in HIV-1 Infected Thai Adults

Characteristics/Duration	Week 12				Week 24
	Univariate Analysis		Multivariate Analysis		Univariate Analysis		Multivariate Analysis
	Beta	P value	Beta	P value	Beta	P value	Beta	P value
Age, years	0.13	0.115			0.04	0.628
Gender	0.04	0.653			0.11	0.181
Body weight, kg	−0.04	0.634			0.01	0.883
Height, cm	−0.16	0.048			−0.04	0.681
Hemoglobin, g/dL	−0.04	0.622			−0.23	0.009	−0.27	0.002
Blood Urea Nitrogen, mg/dL	−0.01	0.948			0.02	0.865
Serum creatinine, mg/dL	−0.06	0.504			−0.21	0.016	−0.25	0.004
Albumin, g/dL	−0.01	0.965			−0.01	0.887
Globulin, g/dL	0.19	0.022	0.20	0.018	0.19	0.030
Direct bilirubin, mg/dL	−0.05	0.555			0.03	0.721
Total bilirubin, mg/dL	−0.06	0.495			0.02	0.806
Alkaline phosphatase, U/L	0.03	0.747			0.01	0.963
Aspartate aminotransferase, U/L	−0.06	0.488			−0.09	0.339
Alanine aminotransferase, U/L	−0.08	0.360			−0.09	0.313
ABCA1 (c.4760A>G, rs2230808)	0.02	0.791			−0.06	0.458
ABCC2 (g.68231A>G, rs3740065)	−0.01	0.905			0.07	0.423
ABCC2 (c.-24C>T, rs717620)	−0.03	0.687			−0.07	0.437
ABCC4 (c.3348A>G, rs1751034)	−0.01	0.988			−0.07	0.398
SULT1A1*2 (c.638G>A, rs1042028)	−0.10	0.220			−0.19	0.027	−0.17	0.049
SULT1A1 copy number	−0.11	0.204			−0.05	0.595
UGT2B7 (c.-161C>T, rs7668258)	−0.01	0.994			0.11	0.207
UGT2B7, (c.211G>T, rs12233719)	−0.01	0.898			0.08	0.359
UGT2B7, (c.372A>G, rs28365063)	−0.04	0.601			0.07	0.421
UGT2B17 copy number	0.07	0.395			0.02	0.774

Abbreviations: CD4, cluster of differentiation 4; HIV, human immunodeficiency virus; RNA, ribonucleic acid; ARV, antiretroviral; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ABCB1, ATP Binding Cassette Subfamily B Member 1; ABCA1, ATP binding cassette subfamily A member 1; ABCC2, ATP Binding Cassette Subfamily C Member 2; SULT1A1, sulphotransferase 1A1; UGT2B7, UDP Glucuronosyltransferase Family 2 Member B7.

Figure 1 Influence of SULT1A1*2 (c.638G>A) on median plasma efavirenz (EFV) concentrations at week 12 and 24. Dash lines represent the therapeutic window for EFV (1–4 mg/L). (A) Median plasma EFV concentrations compared between groups (p=0.638) at week 12. (B) Median plasma EFV concentrations were significantly lower in heterozygous patients (638G/A; 2.18 mg/L, IQR 1.44–2.60, p=0.048) compared to those not carrying the variant (638G/G; 2.33 mg/L, IQR 1.57–4.21).

Figure 2 Influence of SULT1A1 copy number variation on median plasma efavirenz (EFV) concentrations at week 12. Dash lines represent the therapeutic window for EFV (1–4 mg/L). A comparison of SULT1A1 copy number (CN) and median plasma EFV concentration at week 12. Median plasma EFV concentrations were significantly lower in patients with CN≥3 (p=0.046), CN=3 (p=0.019), and CN=3+4 (p=0.015) compared to those carrying CN=2.

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