Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics

Table 1 Summary of most relevant genetic determinants of antiretroviral drug pharmacokinetics and toxicity

Drug/drug class	Gene, allele(s)/SNPs	SNP	Reported associations	Additional observations	Ref.
Abacavir	HLA-B*5701	2395029	↑ risk of HSR	Cost effective test and included in all ART guidelines	[11-13]
Tenofovir	ABCC2 (MRP2)1249G > A	2273697	↑ risk of renal proximal tubulopathy in French populations	To be confirmed in other populations	[14,15]
Lamivudine, Zidovudine	ABCC4 (MRP4) 3724G > A, 4131T > G	22736973742106	↑ intracellular exposure of stavudine triphosphate	Uncertain clinical significance	[15,53]
NRTIs	TNFα238G > A	361525	Earlier onset of lipoatrophy	Negative findings reported by others	[16-20]
Stavudine, NRTIs	IL1β+ 3954C > T	1143634	↓ risk of lipodystrophy in Spanish populations	To be confirmed in other populations	[20]
NRTIs	MMP1-16071G > 2G	1799750	↑ risk of lipodystrophy in Spanish populations	To be confirmed in other populations	[21]
Stavudine, Zidovudine	TS↓ expression and MTHFR 1298A > C↑ activity genotypes	1801131	↑ risk of lipodystrophy and peripheral neuropathy in Spanish populations	To be confirmed in other populations	[24,25]
NRTIs	LPS-binding protein (LBP)T > C	2232582	↑ risk of lipodystrophy in Spanish population	To be confirmed in other populations	[22]
NRTIs	Mitochondrial DNA (haplogroup T): MTND1*LHON4216C, MTND2*LHON4917G, 7028C > T, 10398G > A, 13368G > A	28357980	↑ risk of peripheral neuropathy	Tissue specific mitochondrial DNA depletion may also play some role in NRTI toxicity	[7,26,27]
NRTIs	HFE845G > A		↓ risk of peripheral neuropathy	Negative findings reported by others	[28,29]
NRTIs	CFTR 1717-1G > A, IVS8 5T, SPINK-1 112C > T		↑ risk of pancreatitis	Reported also in the general population	[30]
Nevirapine	HLA-DRB1*0101		↑ risk of HSR and hepatotoxicity	CD4 cell % > 25% associated with ↑ risk	[31,32]
Nevirapine	HLA-cw8		↑ risk of HSR in Italian and Japanese populations		[33,34]
Nevirapine	CYP2B6 983T > C	28399499	↑ risk of HSR in Malawian and Ugandan populations	Stevens-Johnson syndrome or toxic epidermal necrolysis, but no other HSR	[37]
Nevirapine, Efavirenz	ABCB1 (MDR1) 3435C > T	1045642	↓ risk of hepatotoxicity		[35,36]
Efavirenz	ABCB1(MDR1) 3435C > T	1045642	↓ plasma exposure	Negative findings reported by some authors	[51-53]
Efavirenz	CYP2B6 *1/*1 haplotype		↓ plasma concentrations	In patients receiving antituberculosis treatment	[45]
Efavirenz	ABCB1 (MDR1 3435C > T	1045642	↑ HDL-cholesterol in Spanish populations	To be confirmed in other populations	[60]
Efavirenz	CYP2B6 516G > T, 983T > C	3745274 28399499	↑ plasma exposure and ↑ risk of CNS side effects	Reports of successful efavirenz dose individualization	[39,42,44,46,48,49]
Efavirenz	CYP2A6 48T > G, UGT2B7 735A > G	2839943328365062	↑ plasma concentrations in Black and White, but not in Hispanic individuals from the United States	To be confirmed in other populations	[47]
Efavirenz, Nevirapine	CYP2B6 516G > T, 983T > C	28399499	↑ plasma exposure in African populations	To be confirmed in other populations	[43]
NNRTIs	ABCA1/Hepatic Lipase (LIPC)/Cholesteryl Ester Transfer Protein (CETP)	41493131735393764261	↑ LDL-cholesterol in Spanish populations	To be confirmed in other populations	[61]
PIs	ABCA1 2962A > G		↑ risk of hyperlipidemia		[60]
PIs	CETP 279A > G		↑ risk of hyperlipidemia		[60]
PIs	APOA5-1131T > C, 64G > C	662799	↑ risk of hyperlipidemia		[60,62]
Antiretrovirals	APOE/LDL Receptor (LDLR)	4055092228671	↑ risk of trunk fat gain in Spanish populations	To be confirmed in other populations	[23]
PIs	APOC3 482 C > T, 455 C > T, 3238 C > G	285411728541165128	↑ risk of hyperlipidemia		[18,63]
PIs	APOE ε2 and ε3 haplotypes		↑ risk of hyperlipidemia		[18]
Antiretrovirals	Insulin Receptor Substrate 1 (IRS1)	1801278	↑ risk of limbs lipoatrophy in Spanish populations	To be confirmed in other populations	[23]
Raltegravir	UGT1A1*28/*28		↑ modestly plasma levels	Clinically no significant	[57]
Atazanavir, Indinavir	UGT1A1*28		Unconjugated hyperbilirubinemia and jaundice		[54,55]
Atazanavir	ABCB1 (MDR1) 3435C > T	1045642	Unconjugated hyperbilirubinemia and jaundice	↑ plasma levels	[57]
Atazanavir	ABCB1 (MDR1) 2677 G > T	2032582	↑ intracellular/plasma concentration ratios	For GG homozygous as compared with GT and TT genotypes	[58]
Nelfinavir	CYP2C19*2 (681G > A)	4244285	↑ drug exposure in Italian and multiracial Americans	To be confirmed in other populations	[39]
Indinavir	CYP3A5*3 (A6986G)		↑ oral clearance	To be confirmed in other populations	[53]
Maraviroc	CCR5WT/Δ32		No effect on virologic response	Clinically not significant	[7]

SNP: Single-nucleotide polymorphisms; HSR: Hypersensitive reaction; ART: Antiretroviral therapy; CNS: Central nervous system; NRTIs: Nucleoside reverse transcriptase inhibitors; NNRTIs: Non-nucleoside reverse transcriptase inhibitors; PIs: Protease inhibitors.