introduction of highly active antiretroviral therapy ( haart ) has drastically reduced mortality associated with hiv infection , but variability in efficacy and toxicity is challenging . the advances in molecular biology has changed pharmacogenetics to a great extent to develop pharmacogenomics1 . host genetic factors are accountable for the variability in antiretroviral ( arv ) response along with sex , body mass index , heredity and disease progression . a single - nucleotide change is a dna sequence variation occurring commonly within a population at the same locus of the gene which may alter functioning of the protein product extensively . single - nucleotide change hardly affects functioning of the protein produced by that gene , but some changes affect functioning . single nucleotide polymorphisms ( snps ) are significant with respect to genes of drug metabolic pathway including enzymes , drug carrier proteins involved in pharmacokinetics and disease progression . genetic variations in pathways of drug absorption , disposition , metabolism and excretion ( adme ) contribute to inter - patient differences . therefore , genes encoding for transport proteins , drug metabolizing enzymes or nuclear receptors have been the main targets of hiv pharmacogenomic studies . so far , numerous associations of snps with susceptibility to arv drug adverse reactions or risks of virological failure have been reported4 . this review focuses on some important aspects of pharmacogenomics to maximize efficacy and minimize toxic effects of haart . combination antiretroviral therapy ( cart ) for hiv - haart or cart has improved the prognosis of hiv infection close to normal life expectancy . with haart , there are six categories of drug regimens available as follows : ( 1 ) nucleoside reverse transcriptase inhibitors ( nrtis ) , ( 2 ) non - nucleoside reverse transcriptase inhibitors ( nnrtis ) , ( 3 ) protease inhibitors ( pis ) , ( 4 ) integrase inhibitors ( iis ) , ( 5 ) fusion inhibitors ( fis ) , and ( 6 ) chemokine receptor antagonists . the choice of treatment is mainly influenced by hiv disease stage , co - morbidities , co - medication with potential drug - drug interactions , pregnancy or pregnancy potential , expected cart toxicity , and results of genotypic resistance testing and synergism / antagonism of the combination on hiv virus life cycle . summary of genetic variants associated with antiretroviral ( arv ) pharmacokinetics , toxicity and efficacy pharmacogenetics of adverse reactions due to haart 1 . nucleoside reverse transcriptase inhibitors ( nrtis ) : nrti is a nucleoside analogue antiretroviral drug and its chemical structure constitutes a modified version of a natural nucleoside . these inhibit viral replication of retroviruses by stopping extension of oligomer due to absence of 3 hydroxyl group essential for addition of incoming new nucleotide . this prevents further synthesis of viral nucleic acid by interfering with the reverse transcriptase enzyme45 ( fig . these drugs get activated on endocytosis after phosphorylation to form active triphosphate compound ( pro - drugs ) . the known drug toxicities are linked with lipid metabolism , liver steatosis and lactic acidosis . additional evidence relates nrti drugs to disruption of mitochondrial function , oxidative stress and peripheral neuropathy46 . zidovudine ( zdv ) ( azidothymidine , azt ) - thymidine analogue - zdv has been prescribed after u.s . food and drug administration ( fda ) approval in 1987 as a part of drug regimen to treat hiv infection , till it was found more harmful than tenofovir47 . zdv was found to be associated with severe anaemia in a randomized trial in untreated hiv patients using efavirenz ( efv ) in addition to zdv + lamivudine ( 3tc ) / tenofovir ( tdf ) + emtricitabine ( ftc ) where zdv was removed in 5.5 per cent population under study48 . a previous study showed that 16.2 per cent of patients developed zdv induced anaemia in the population of eastern india49 , 58 per cent of the patients on zdv showed reduced viral load ( < 400 copies / ml ) as compared to 71 per cent cases on tdf only because zdv had to be withdrawn in 11 per cent ( vs 5% ) of the cases after drug adversities in 144 wk49 . observed zdv related toxicities include drop in haemoglobin level and neutrophils count , and nausea due to gastrointestinal disturbances within a few weeks on initiation of the trial . also , fat deposition in upper and lower extremities was significantly reduced on zdv treatment50 . a pharmacogenetic study has reported higher levels of zdv - triphosphates ( up to 49% ) in hiv cases heterozygotes for abcc4 g3724a on zdv treatment as compared to wild type gg homozygote51 . another variant abcb1 gt or tt has shown significantly reduced levels of hiv viral load than that in individuals having wild type gg genotype52 . kwara et al53 have shown 196 per cent oral drug clearance associated with ugt2b7 * 1c carriers on zdv therapy when compared to non carriers . these studies emphasize on extensive analysis using large cohorts for understanding potential role of pharmacogenomic factors in zdv pharmacokinetics and pharmacodynamics5 . stavudine ( d4 t ) - thymidine analogue - stavudine ( 2,3-didehydro-2,3-dideoxythymidine ) was made available for patients showing virological failure or intolerance to zdv after its approval in may 199654 . therefore , in 2009 , the world health organization ( who ) restricted its use due to long - term , irreversible side effects55 . lamivudine ( 3tc ) - cytidine analogue - lamivudine ( 2,3-dideoxy-3-thiacytidine ) is another nucleotide analogue used in combination therapy for delaying developments of acquired immunodeficiency syndrome ( aids ) and hence , avoiding disease related complications or cancer . higher intracellular concentrations of 3tc - triphosphate have been reported to be associated with multidrug resistance protein 4 ( mrp4 ) t4131 g change and mrp2 polymorphism49 . tenofovir disoproxil fumarate ( tdf ) - adenosine analogue - tenofovir , one of the most effective and commonly prescribed antiretroviral drugs belongs to a class of nucleotide reverse transcriptase inhibitors ( ntrtis ) . nucleotide analogues have phosphate group in addition to pentose and nucleic base of nucleoside . unlike nucleoside analogues , ntrtis are chemically preactivated and thus require less processing in the body . a single g > a substitution at 1249 nucleotide of atp - binding cassette , sub - family c , member 2 ( abcc2 ) gene is reportedly linked with tdf adverse reaction causing renal tubulopathy6 . more recently , a nave association between abcc4 3463a > g genotype and renal toxicity has been reported showing tenofovir concentrations 35 per cent higher in carriers of the 3463 g variant44 . abacavir ( abc ) - guanosine analogue - hypersensitivity to abc occurs in about five per cent of hiv infected patients usually by the second week of abc treatment . in some cases , a polymorphism in hla gene hla - b*5701 needs to be screened prior to initiation of abc treatment to avoid hypersensitivity reaction . an indian study58 demonstrated that hla b17 frequency in hiv patients on antiretroviral therapy was due to the different composite ethnic groups studied . the testing for hla b17 antigen along with hla b*5701 allele subtype can be used as pharmacogenetic testing to prevent abacavir hypersensitivity reaction among indian patients58 . 335 t > g polymorphism in p5 gene of hla is preferred snp marker over hla b*5701 for abc sensitivity due to simplicity and economicity101112 . non - nucleoside reverse transcriptase inhibitors ( nnrtis ) : non - nucleosides are directly active drugs as against prodrug nrtis . these prevent hiv replication by targeting the enzyme reverse transcriptase , binding to a site near to but different from the active site for substrate . snps associated with these isoenzymes play crucial role in inter - individual differences in metabolism and disposition of nnrtis59 . polymorphisms result in decreased expression of enzymes and their activity in liver microsomes . as a result also , genes encoding drug transporters and hla are considered in the pharmacogenetic studies of nnrti . snps in mdr1 gene , which encodes for p - glycoprotein ( p - gp ) affect oral absorption and desorption of nnrtis . the association between variants of mdr1 gene and nnrti plasma concentrations has been studied comprehensively44 . nevirapine ( nvp ) - in 1997 , nvp was approved as nnrti60 . in developing countries , it is the preferred first line drug in combination with two nrtis due to its efficacy , moderate price and adjustable dosage60 . about 15 - 20 per cent patients experience rash and nvp needs to be withdrawn in about 7 per cent of them61 . nvp - induced rashes were reported in 2.14 per cent of hiv positive individuals from india62 . the polymorphism abcb1 - 3435c > t is linked with a decreased risk of hepatotoxicity in patients receiving nvp2530 . nvp plasma concentration is affected by g516 t and 983 t > c substitutions in cyp2b6 gene . also , significantly higher nvp plasma levels are reported in black patients heterozygous for t983c snp1617 . although sex , age , body mass index , habits , habitat and pathological liver condition are major criteria in influencing pharmacokinetics of nvp , but in most of the studies only body weight is included294457 . efavirenz ( efv ) - efv is the first line drug for untreated hiv infected cases . efv shows a narrow therapeutic range and there is a potential risk of high level of therapeutic concentrations that are related with virological failure or neurological manifestations . the g516 t snp in cyp2b6 ( cyp2b6 * 6 ) is reported to have a major impact on the pharmacokinetics and pharmacodynamics of efv65 . black patients are predisposed to the cns effects due to high prevalence of the genotype cyp2b6 - 516tt1819 . also , there is snp variability due to 785 a > g , 983 t > c , 593 t > c and 1132 c > this affects its pharmacokinetics with increased drug levels , which result in cns events or virological failure , necessitating cyp2b6 allele genotyping . host genetic code on invading cd4 cell and utilizes host cell machinery for its replication . the viral gag - pol polyprotein is excised into active protein particles of newly formed virus by viral protease , a molecular scissor . this step is inhibited by blocking the protease enzyme using pis by preventing a proteolytic splicing and results into non - infectious virus particles ( fig . 3 ) . toxic effects of pis include lipodystrophy , dyslipidaemia , tolerability problems and gastrointestinal disturbances67 cyp3a4 also metabolizes both simvastatin and lovastatin . when pis act as inhibitor of cyp3a4 , the levels of simvastatin and lovastatin may increase drastically6970 pis are substrate analogue ( mimic protein cutting site ) , and prevent generation of new viral proteins . ritonavir ( rtv ) - ritonavir is included in combinational regimen because it blocks host enzymes involved in metabolism of pis . the primary role of rtv in boosted pi regimens is to improve the pharmacokinetics of the second pi . rtv inhibits host enzymes of drug metabolic pathways causing their levels to rise in bloodstream , and increasing efficacy of other pis with reduced dose and frequency rendering them more compliant . these increase cholesterol and triglycerides levels , cause abnormal fat deposition in various parts of the body , and diabetes . these can be associated with polymorphisms of genes like atp - binding cassette transporter a1 ( abca1 ) , apolipoprotein a5 ( apoa5 ) , apo lipoprotein c3 ( apoc3 ) , apo lipoprotein e ( apoe ) , and cholesterol ester transfer protein ( cetp)73 . atazanavir ( atv ) - in march 2004 , atv arrived in market as daily prescription in single dose . fifty per cent of cases on atv show rise in bilirubin levels and above one third have grade 3 - 4 . some patients even develop jaundice as hepatic conjugation is hampered due to a mechanism similar to gilbert 's syndrome . this side effect is provoked by competitive inhibition of udp glucuronosyl transferase 1 family polypeptide a1 ( ugt1a1 ) , the microsomal enzyme causing glucuronidation , which allows bilirubin excretion . a previous indian study has reported increased prevalence of of ( ta)7/(ta)7 genotype in neonates ( allele frequency 0.366)38 . the presence of snp ugt1a1 * 28 is strongly associated with the occurrence of jaundice because of decreased enzyme activity525780 . indinavir ( idv ) - highly penetrating idv reaches genital compartments and cns , but it is not preferred nowadays39 . this medicine needs to be used with caution in india due to presence of extensive integrase inhibitors ( iis ) : hiv integrase is an important enzyme in its replication through integrating viral dna with host genome83 . integrase inhibitor is a desirable anti - hiv drug as integrase enzyme is absent in human cells ; its selective inhibition without side effects is possible ( fig . iis inhibit enzyme activity ( bind to enzyme ) and prevent insertion of proviral dna . integrase catalyses the step - wise process of integrating hiv-1 dna into the host genome . in the process , assembly of integrase with viral dna forms stable pre - integration complex , which follows endonucleolytic processing of the viral dna ends , and joining of the viral and host dnas . covalent bonding takes place in 5 phosphate groups exposed on nicking cellular dna strands of host and viral dna to produce provirus . ral is a substrate of the p - gp , and consequently , polymorphisms in transport proteins may explain the large intra- and inter - individual variations of ral exposure8586 . a recent study in spanish hiv ral - cohort reported that the polymorphism at abcb1 - 3435c > t was associated with ral concentrations43 . patients carrying ct or tt genotypes displayed lower median ral concentrations than those with the cc genotype . although pharmacokinetic / pharmacodynamics ( pk / pd ) analyses do not suggest a threshold ral concentration associated with reduced efficacy , patients carrying ct / tt genotypes at the p - gp gene might be more prone to virological failure443 . ugt1a1 * 28/*28 genotype is associated with higher ral plasma concentrations compared to that of ugt1a1 * 1/*1 genotype8788 . fusion inhibitors ( fi ) : thirty - six amino acids long peptide of the fi enfuvirtide ( t-20 ) is similar to a portion of gp41 , necessary for binding to heptad repeat 1 ( hr1 ) . it interferes with hr1 and hr2 interaction and thereby , inhibiting the conformational change crucial for viral fusion to cd4 cells . its high cost , intolerance on long term use , complex mode of administration and limited pharmacokinetic properties are the limiting factors , and in future , studies should focus on these aspect to enhance its clinical advantage89 . 6 . entry inhibitors ( ei ) : hiv enters human body through fusion of viral envelope proteins with binding domain on host cd4 + ( cluster of differentiation 4 ) cell . eis interfere with this fusion step and stop virus from entering into the cell , thereby restricting hiv from infecting a cell and multiplying . eis mainly target either the viral envelope glycoprotein gp120 or gp41 or the c - c chemokine receptor ccr5 or cxcr4 receptors on a cd4 cell surface90 . maraviroc ( mvc ) - maraviroc belongs to entry inhibitors called as ccr5 receptor antagonist . hiv makes entry into host cell using a ccr5 receptor present on cd4 + immune cells . mvc prevents entry of hiv by inhibiting its fusion with the ccr5 receptors ( fig . it allosterically binds to ccr5 by inducing conformational changes within ccr5 and hence , inhibiting its binding to viral gp12091 . it acts against ccr5 tropic viral strains but is inactive against cxcr4 tropic hiv strains . an allele ccr5 of the -chemokine receptor gene ccr5 has been found to confer protection against hiv-192 . in europeans the prevalence of this allele is 5 - 14 per cent but is uncommon in africans and asians93 . its sporadic occurrence in southern and northern parts of india presume caucasian admixture92 . the hiv r5 entry is prevented because of 32 deletion leading to a non - functional receptor . homozygosity for this allele gives strong protection against hiv infection whereas the heterozygosity is associated with milder disease progression94 . however , genetic variations in the ccr5 gene have not been shown to affect virological response to mvc95 . on the other hand , mvc is substrate of cyp3a4 and p - gp ; hence , dose adjustment is frequently required when co - administered with drugs that alter its pharmacokinetics9697 . mvc is identified as substrate of the transport protein oatp1b1 and the variation 521t > c is linked with higher mvc plasma levels98.thus , the only genetic test that is mandatory to perform before starting mvc treatment is the determination of viral tropism499 . it prevents gp120 from binding to the ccr5 co - receptor and prevents the fusion peptide from gp41 inserting into the cell membrane . the objective of any therapy is to maximize the therapeutic outcome and to minimize the side effects . the side effects like cutaneous hypersensitivity may be avoided with proper genetic testing which predisposes to susceptibility such as hla - b*5701 associated abc adverse reaction . similarly , certain drugs like maraviroc may not be prescribed to hiv positive individuals with ccr5 tropic hiv . however , a large number of haart drugs show change in pharmacokinetics due to variations in genes of drug metabolic pathway enzymes like cyp450 , atp binding cassette and ugta1 . individualized approach to personalized haart is influenced by host factors and is known as pharmacogenomics . application of pharmacogenomics with understanding of medicine , viral characteristic of hiv is at the doorstep to guide the personalized prescription in which the right medication will be given to the right person . several measures need to be taken for application of pharmacogenetic research in making a genetic test available for public . many factors affect successful translation such as pharmacodynamics and pharmacokinetic properties of drug adversities , laboratory facilities , quality assurance and quality control ( qa and qc ) measures and type of tests100 . the reported associations have to undergo stringent validation in independent , ethnically diverse populations having highest number of hiv positive individuals .
combination therapy with three drug regimens for human immunodeficiency virus ( hiv ) infection significantly suppresses the viral replication . however , this therapeutic impact is restricted by adverse drug events and response in terms of short and long term efficacy . 
 there are multiple factors involved in different responses to antiretrovirals ( arvs ) such as age , body weight , disease status , diet and heredity . 
 pharmacogenomics deals with individual genetic make - up and its role in drug efficacy and toxicity . in depth genetic research 
 has provided evidence to predict the risk of developing certain toxicities for which personalized screening and surveillance protocols may be developed to prevent side effects . here 
 we describe the use of pharmacogenomics for optimal use of haart ( highly active antiretroviral therapy ) .