The Pharmacogenomics of HIV Therapy

¼ patients with primary HIV infection, The pharmacogenomics of HIV ¼ patients with asymptomatic HIV infection and therapy ¼ patients with symptomatic HIV disease or AIDS. M Pirmohamed and DJ Back The recommendations of the British HIV Association (BHIVA; http://www. Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton bhiva.org) are summarised in Table 2. Street, Liverpool, UK The putative benefits of treatment during primary HIV infection (PHI) have AIDS turned 20 years old on 5 June use of pharmacogenomics has the to be weighed against the known risks 2001; it has to date claimed the lives of potential to resolve some of the prob- of toxicity. Furthermore, despite sup- 21 million individuals, mostly within lems with currently available anti-HIV pression of viral load, HIV replication Africa.1 During the last 20 years, there drugs as well as with the new drugs may continue with an associated risk has been remarkable progress in the being developed. An additional area that of development of drug resistance or therapy of HIV disease. At the beginning, needs to be considered in relation to HIV transmission of drug resistant virus.6 It all that was offered was prophylaxis and therapy is the genetic diversity of the has to be assumed that lifelong treat- treatment of the opportunistic infections virus itself. The purpose of this review is ment will be required even when that are the hallmark of immunodefi- to highlight potential areas where phar- initiated in PHI. All patients with late ciency. The first drug that was active macogenomics may be of use in both disease and/or symptomatic HIV with Ϫ against HIV, zidovudine (AZT), was maximising the efficacy and minimising a CD4 count below 200 cells ␮l 1 or licensed in 1987 in the US. Since then, the toxicity of antiretrovirals, in parti- who have been diagnosed with AIDS advances have not only involved the cular to: or severe/recurrent HIV related illness development of new drugs, but also the should start therapy. The debate of ¼ use of these drugs in appropriate combi- improve the failure rate of current when to start treatment tends to nations. The use of so-called highly drug regimes; centre on patients with established ¼ active antiretroviral therapy (HAART) overcome the problems associated HIV infection but who are asympto- since 1995 has led to a remarkable with kinetic variability of antiretrovir- matic. Ultimately the decision must be improvement in the prognosis of HIV dis- als; and to ensure that the benefits of currently ¼ ease:2 there has been a decrease in AIDS- reduce the short- and long-term tox- available therapies outweigh the risks related deaths, reduction in the use of icities of the drugs. of deferring therapy. drugs for opportunistic infections, and a Evidence is overwhelming that decrease in the numbers of patients hos- CURRENT PRACTICE AND patients should commence therapy 2,7,8 pitalised with AIDS-related illnesses. HIV PROBLEMS OF ANTI-HIV with a HAART regimen. Any can now be classified as a chronic dis- THERAPY HAART regimen should be individual- ease; until a cure is found, patients are The currently licensed antiretrovirals ised in order to achieve the best likely to require life-long therapy. How- fall into three classes, nucleoside potency, adherence and tolerability, to ever, despite these undoubted advances, reverse transcriptase inhibitors minimise toxicity and avoid problems there are many issues that need to be (NRTIs), non-nucleoside reverse tran- of drug–drug interactions. The aim Ͻ resolved, including the problems asso- scriptase inhibitors (NNRTIs) and pro- must be to achieve a viral load 50 Ϫ1 ciated with long-term efficacy and tox- tease inhibitors (PIs)4 (Table 1). With HIV-RNA copies ml at 6–9 months. 4 icity. the available drugs, eradication of HIV The choice of initial therapy is: Pharmacogenomics has been widely is not likely to be possible. The aim of ¼ 2NRTIs ϩ NNRTI hailed as a means to improve prescribing treatment is therefore to prolong life ¼ 2NRTIs ϩ PI for all drugs.3 However, pharma- and improve the quality of life by ¼ 2NRTIs ϩ 2PIs (the primary reason cogenomics is likely to be particularly maintaining suppression of viral repli- for combining PIs is to improve 5 useful for drugs that have variable kin- cation for as long as possible. There is pharmacokinetics. There is wide use etics and dynamics, and a narrow thera- controversy as to the stage of disease of ritonavir as a pharmaco- peutic index. Anti-HIV drugs certainly fit drug therapy should be commenced enhancer). this category. Although there are many and differences may exist in treatment ¼ 3NRTIs. issues that need to be handled in the guidelines. The three groups of treat- next 20 years in the fight against HIV,1 ment naive patients for whom treat- Despite the undoubted short-term individualisation of therapy through the ment guidelines are required are: efficacy of these combinations, it has HIV pharmacogenomics M Pirmohamed and DJ Back 244

Table 1 Currently licensed antiretroviral drugs viduals, and form the basis for either failure or toxicity of the different Nucleoside reverse Non-nucleoside reverse Protease inhibitors (PIs) drug regimes. transcriptase inhibitors transcriptase inhibitors (NRTIs) (NNRTIs) GENOMICS OF VIRAL RESISTANCE Zidovudine (ZDV) Nevirapine (NVP) Saquinavir (SQV) The goal of antiretroviral therapy is to Didanosine (ddI) Efavirenz (EFV) Ritonavir (RTV) completely suppress viral replication. Stavudine (d4T) Delavirdine (DLV)a Indinavir (IDV) Zalcitabine (ddC) Nelﬁnavir (NFV) If left untreated, HIV replicates at a 13 Lamivudine (3TC) Amprenavir (APV) rapid rate. Taken together with the Abacavir (ABC) Lopinavir & low dose fact that HIV has a high propensity to ritonavir (LPVr) mutate, it is likely that each new virus particle will contain at least one a Not licensed in the UK. mutation.13 During the process of transcription of the proviral DNA from the viral RNA, reverse transcriptase Table 2 Summary of recommendations of when to start treatment (British makes errors relatively frequently. The HIV Association) errors can be of two main types: substi- tutions, where one nucleotide replaces Presentation Surrogate markers Recommendation another and insertions/deletions of one or more nucleoside in the proviral Primary HIV Infection If treatment considered, start as DNA chain. Given the high level of soon as possible, certainly viral replication and turnover within 6 months of con- (typically around 109 viral particles per tracting HIV. day14), this creates the potential for Clinical trial if available. large numbers of genetically distinct Established asymptomatic CD4 Ͼ350 cells ␮lϪ1 Defer treatment. quasi species to be created. Some HIV infection & any viral load mutations result in small changes in CD4 200–350 cells ␮lϪ1 Start treatment taking into the structure of proteins such as account symptoms, rate of reverse transcriptase and/or protease. CD4 decline, viral load and If these changes are at the site of patient wishes action of antiretroviral drugs, then it is CD4 Ͻ200 cells ␮lϪ1 Treat possible that one or more drugs will & any viral load not bind correctly to the target protein. Ongoing viral replication will Symptomatic HIV or AIDS Treat occur in the presence of drug and a resistant quasi species will become the dominant form of the virus in the patient. The clinical implication of this is that once resistance develops, been shown in a meta-analysis that HAART; although many of these the treatment will fail and disease may only 46% of patients were able to adverse effects are minor and depen- progress.15 Some of the key mutations reach the targeted HIV viral load (Ͻ50 dent on dose, they nevertheless affect associated with the development of copies mlϪ1) by 48 weeks.9 Even if the tolerability of HAART, and hence resistance are shown in Table 3. there is initial success, many patients adherence to it.11 Recently, and per- The importance of viral resistance in eventually have to change their initial haps more worrying in respect of the reducing success rates is evidenced by drug regime either because of viral long-term effects of HAART, have been the fact that patients who are treat- rebound or toxicity. For example, in reports of lipodystrophy, a fat redistri- ment-experienced have lower success the Swiss cohort study, rebound HIV bution syndrome associated with rates on second-line and salvage ther- viraemia was approximately 10% per metabolic abnormalities that may apies.16 Genotypic assays that detect year in treatment-naive patients com- have consequences for the develop- mutations have been shown to predict mencing therapy, and 20% per year ment of atherosclerosis in this patient response to antiretrovirals.17–21 For in treatment-experienced patients cohort.12 The levels of the drugs example, among patients who experi- switching therapy.6 In another cohort, within the blood and tissues, how they enced HAART failure, viral suppression viral rebound was observed in 50% of are handled by the body, and the (Ͻ500 copies mlϪ1) at 12 weeks was patients within 12 months of achiev- effect they have on host biological more common among patients for ing undetectable viral RNA.10 Toxicity processes (as opposed to the virus) are whom genotypic anti-retroviral resist- is observed in many patients on all subject to variation between indi- ance testing and clinical judgment

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Table 3 Mutations associated withresistance to approved antiretroviral drugs

Drug Mutation selected Cross resistance

ZDV M41L, D67N, K70R, T215Y/F, K219Q/E d4T, highly resistant virus to other NRTIs ddI K65R, L74V, M184V ddC ddC K65R, T69D, M184V 3TC d4T K70R, T125Y/F ZDV 3TC M184V ddC ABC K65R, L74V, Y115F, M184V 3TC, ddI, ddC

NVP L100I, K103N, V106A, V108I, Y181C/I, Y188C/L/H, G190A/S DLV (K181C, K103N), EFV (K103N) DLV K103N, Y181C/I, P236L NVP (K103N, Y181C), EFV (K103N) EFV L100I, K103N, V108I, P225H DLV, NVP (K103N) SQV L10I/R/V, K20M/R, L24I, D30N, M36I, G48V, I54V/L, L63P, V82A/T/F, I84V, L90M RTV K20M/R, V32I, L33F, M36I, M46I/L, 154V/L, L36P, A71V/T, V82A/T/F, 184V, L90M IDV L10I/R/V, K20M, L24I, V32I, M36I/L, M46I/L, I54V/L, L63P, A71V/T, V82A/T/F, I84V, L90M NFV D30N, M36I/L, M46I/L, L36P, A71V/T, V77I, I84V, N88S, L90M APV L10I/R/V, M46I, I47V, 150V, I84V LPV L10I/R/V, K20M/R, L24I, M46I/L, I54V/L, L63P, A71V/T, V82A/T/F, I84V, L90M

The mutations indicated in bold are the key mutations associated with resistance to the individual drugs. were used to guide the choice of a and C HIV-1 subtypes show variations studied further.25 First, genotyping second-line or subsequent regimen in the order of 10–30%.24 Interest- will only detect the predominant viral (34%) than among those whose treat- ingly, these variations are most pro- populations in circulation, with those ment was determined by clinical judg- nounced in matrix proteins, which representing less than 10–50% of the ment alone (22%).21 Furthermore, can show up to 27% variation, and viral population being missed. The cost-effectiveness analysis using mod- least pronounced in essential enzymes importance of these minor subtypes els derived from patient data has such as reverse transcriptase, which on long-term prognosis needs further shown that genotypic testing for sec- shows 7–9% variation. A recent study study. Second, the results of genotypic ondary resistance increases life expect- has shown that the protease from the testing need careful and expert ancy by 3 months, at a cost of $17 900 A subtype, which differed from the interpretation, which may not be per quality-adjusted life year gained.22 consensus B subtype sequence in available in all centres. Furthermore, in Primary resistance testing was less seven amino acid positions, had 1.5–5 vitro testing does not take into account cost-effective, although this was times higher vitality than the B sub- the synergy between the different dependent on the prevalence of resist- type.24 Similarly, the C subtype, which drugs used in combination. Pheno- ance in primary isolates, the cost-effec- differed in four amino acid positions, typic tests although easier to interpret tiveness increasing as the background had 4–11 times higher vitality than and equivalent to genotypic testing26 resistance rate increased. Based on the B subtype.24 Thus, although the are more expensive than genotypic efﬁcacy and cost-effectiveness data, current practice of resistance testing tests. Finally, although resistance test- resistance testing is now rec- has been shown to be clinically and ing is indicated in patients who have ommended in several guidelines.5,23 cost-effective in the Western world, failed on one or more treatment Indeed, its effectiveness is likely to be whether this holds true in Africa, regimes, its value in the detection of enhanced by concomitant therapeutic where HIV is exerting the greatest bur- primary resistance, ie before drug ther- drug monitoring.17 den, is unclear. Nevertheless, determi- apy has begun, is unclear. Clearly these guidelines have been nation of variation in essential viral developed for use in the US and West- enzymes such as the protease, may INTERINDIVIDUAL VARIABILITY ern Europe. It is important to note in allow the development of newer IN RESPONSE TO these countries, the B subtype of HIV- agents with a greater ability to inhibit ANTIRETROVIRALS: IMPACT OF 1 accounts for the vast majority of the proteases from the different sub- GENOTYPE ON infections.24 By contrast, in the north- types, and thereby improve long-term PHARMACOKINETICS ern part of sub-Saharan Africa, the A outcome. Among HIV-infected patients there is subtype predominates, while in south- Although viral resistance testing is considerable variability in the ern African, the C subtype is most now recommended in guidelines, response to antiretroviral therapy and prevalent. The entire genomes of A, B there are several issues that need to be one critical factor is the marked inter-

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patient difference in plasma concen- CYP2D6 activity can give rise to drug CYP3A activity exhibits considerable trations arising from the same drug accumulation due to reduced clear- interindividual variability and this is regimen.4 Although this is seen with ance.34 However, most of the drugs assumed to reflect the combined effect all three classes of drugs (NRTIs, metabolised by CYP2D6 have a wide of modulation by environmental fac- NNRTIs PIs), most attention has been therapeutic index and are amenable to tors and to a large extent so far focused on PIs and NNRTIs for two dose reductions. Allelic variants of unidentified genetic factors. Recently, reasons. Firstly, NRTIs have to be CYP2C9 and CYP2C19 lead to inactive polymorphisms affecting amino acid phosphorylated by cellular kinases to enzyme or enzyme with reduced sequence have been found in CYP3A4 the active triphosphate anabolite, so affinity for substrate.35 This can impact (Table 4) and the contribution of these that plasma concentrations of the par- on dose requirements. alleles to the variability of CYP3A4 ent nucleoside do not reflect the con- Of the human CYP proteins, mem- expression or activity is currently centration of the intracellular active bers of the CYP3A subfamily are of being determined.31 Another drug.27 Secondly, both PIs and NNRTIs major importance since they form the important aspect is the increased are substrates for cytochrome P450 largest portion of the liver (and expression of CYP3A genes by a range (CYP450) isoforms28 and transporter enterocyte) CYP protein.33 Although of drugs. The induction of CYP3A is molecules such as P-glycoprotein and CYP3A4 is most often discussed, the the result of transcriptional activation. multi-drug resistance protein.29,30 human CYP3A subfamily actually con- Recently a number of studies have led There is currently much interest in the sists of three homologous proteins to the identification of a human role of genetic polymorphisms in (CYP3A4, CYP3A5, CYP3A7) encoded orphan nuclear receptor, the pregnane enzymes and transporters in determin- by distinct genes.36,37 CYP3A4, the X receptor (hPXR) as a major activator ing pharmacokinetic variability and in major isoform in the CYP3A family, of CYP3A transcription.39–41 Whether seeking to elaborate how such infor- shows extensive (Ͼ30-fold in some the variability in induction can be mation may be brought to impact on studies) variation in expression. Sev- explained by the recently described HIV patient management. eral allelic variants, which may be polymorphisms in the PXR gene42 functionally active, have been needs further study. Metabolic Enzymes described.31 Additionally, more Possible ethnicity differences in Several polymorphisms that affect recently, the molecular basis of the CYP3A activity have been explored. genes encoding CYP450 enzymes have polymorphic expression of CYP3A5 The probe drug midazolam was simul- been described (Table 4—see Ingel- has been described.38 CYP3A5 is taneously administered intravenously man-Sundberg31). In clinical pharma- expressed in 70% of individuals, and and orally to young healthy European cology, polymorphisms in the gene when present may account for about American men and a similar group of encoding CYP2D6 have attracted half of the variability in CYP3A men of African American descent. Sub- much attention.32 This P450 is respon- activity. CYP3A7 was originally iso- jects were genotyped with respect to sible for the metabolism of more than lated from fetal liver but has sub- CYP3A4*B1. With one exception, the 100 drugs including many CNS and sequently been shown to be present in African Americans possesed a variant CVS drugs.33 Absent or reduced Ͼ50% of adult livers.36 CYP3A4*B1 allele (four heterozygotes

Table 4 Polymorphisms in the cytochrome P450 genes involved in disposition of antiretroviral drugsa

Enzyme Major variant Mutation Consequences Allele frequencies alleles Caucasians Orientals

CYP2C9 CYP2C9*2 R144C Reduced afﬁnity for P450 8–13 0 reductions CYP2C9*3 1359L Altered substrate speciﬁcity 7–92–3

CYP2C19 CYP2C19*2 Aberrant splice site Inactive enzyme 13 23–32 CYP2C19*3 Premature stop codon Inactive enzyme 0 6–10

CYP2D6 CYP2D6*4 Defective splicing Inactive enzyme 12–21 1 CYP2D6*5 Gene deletion No enzyme 4–66 CYP2D6*10 P345, S486T Unstable enzyme 1–250 CYP2D6*17 T107I, R296C, S486T Reduced substrate afﬁnity 0 ? CYP2D6*2ϫN Gene duplication Increased enzyme afﬁnity 1–50–2

CYP3A4 CYP3A4*1B ? 3–40 CYP3A4*2 S222P Reduced substrate afﬁnity 3 0 CYP3A4*3 M445T Not known 0 Ͻ1 aThe data in this table are substantially based on Ingelman-Sundberg.31

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A/G and 10 homozygotes G/G), have been made to develop com- Quantification of MDR1 transcripts in whereas all European Americans were pounds that modulate P-gp activity. PBMCs demonstrated an association homozygous wild type (A/A). Hepatic Examples of so-called first generation between MDR13435 TT genotype and CYP3A activity and systemic clearance P-gp blockers are verapamil and quini- lower MDR1 expression level. The fact of midazolam was about 30% lower in dine. Second generation compounds that nelfinavir plasma levels are low in G/G compared to A/A homozygotes.43 include PSC833, GF120918 and the presence of low P-gp suggests that This modest difference needs to be XR9576. there is an indirect effect of the confirmed in other studies and clearly One important question is whether MDR13435 genotype and the actual there is a requirement for studies allelic variants of MDR1 account for mechanism awaits clarification. For involving antiretrovirals in such popu- some of the interindividual varia- example, there may be overexpression lations. bility in the pharmacokinetics (and of another transporter or upregulation Although polymorphisms in the consequently efficacy) of antiretrovir- of a CYP enzyme. 51 P450 genes have attracted most atten- als. Mickley et al reported the first The frequency of the C3435T tion, it is important to note that evidenceofthepresenceofpolymor- mutation is significantly influenced by phase II enzymes are also involved in phisms in the human MDR1 gene. A ethnicity,55,57,58 marked differences in the metabolism of antiretrovirals. screen of the entire MDR1 gene for genotype and allele frequency being Thus, polymorphisms in genes the presence of SNPs was undertaken seen between African populations and coding for phase II enzymes such as by Hoffmeyer et al.52 SNPs that Caucasian/Asian populations. A high glucuronyl transferase,44 may also be change amino acids and thus possibly frequency of the C allele in African important. have an affect on protein function are subjects implies overexpression of P- located at position A61G in exon 2 gp, and could have considerable impli- P-glycoprotein (P-gp) and at position G1199A in exon 11. cations for use of P-gp dependent P-glycoprotein (P-gp), the product of However, no correlation between drugs (such as antiretrovirals) in indi- the multidrug transporter MDR1 gene, these SNPs and altered function or viduals of African origin. plays a major role in transport of many activity of P-gp has been reported. The Liverpool HIV Group have different substrates including some However, a C3435Tchangeatawobble recently determined drug efflux trans- antiretroviral drugs at compartmental position in exon 26 has been shown porter (P-gp and MRP) expression on and cellular levels.29,30,45–47 At the to have pharmacological conse- PBMCs and the concentration of intestine, P-gp limits drug entry into quences.52 The MDR1 genotype at the saquinavir and ritonavir within cells the body. P-gp is also present in the SNP position correlates with P-gp in HIV patients receiving HAART. apical membrane of many other epi- expression in the intestine, patients Patients with lower MRP1 expression thelial barriers such as the blood– homozygous for the T-allele having had a significantly higher intracellular brain, blood–testis, and maternal–fetal low expression of P-gp. The C3435T concentration of both ritonavir and barrier. In addition, P-gp is expressed SNP has also been shown to be corre- saquinavir than patients with higher in haematopoietic progenitor cells, lated with Pgp expression and func- MRP1 expression. Ritonavir accumu- macrophages and lymphocytes.47 Thus tion on lymphocytes,53 but not in lation was also significantly greater in P-gp limits drug penetration into phar- placenta.54 It is possible that its patients with lower P-gp expression.59 macological sanctuaries and HIV cellu- effects may be tissue-specific, since Clearly, genetic variability and func- lar targets. In these areas, virus may the C3435T polymorphism is a non- tional polymorphisms in ABC trans- persist and replicate, despite apparent coding,non-promoterSNP,andmay porters are relevant pharmacological suppression of replication in plasma. be linked to an SNP that affects gene factors that have to be considered Multidrug transporters such as P-gp expression in regulatory regions of together with drug-metabolising and multidrug resistance associated the MDR1 gene.49 enzymes in order to understand varia- protein (MRP) could play an important Individuals carrying the homo- bility in drug response. Understanding role in lowering therapeutic drug con- zygous low-expressor (T) allele (25% of these genetic parameters could be the centrations at these sites via an efflux the Caucasian population55) show starting point for individualised drug mechanism. In vitro, overexpression of increased digoxin plasma levels due to therapy. P-gp diminishes the intracellular con- increased uptake.52 However, in concentration of protease inhibitors.29 trast, in a study of HIV patients, low P- DISEASE PROGRESSION AND

Therefore differences in P-gp (and gp expression linked to the MDR13435 RESPONSE TO ANTIRETROVIRAL MRP) expression could lead to marked TT genotype was associated with low THERAPY differences in accumulation of antire- plasma levels of nelfinavir and efavir- The progression of HIV infection, as 48,49 56 trovirals in various compartments. enz. Patients with MDR13435 TT well as susceptibility to HIV infection, Because of its association with drug genotype presented median nelfinavir varies widely among individuals. Stud- resistance to cytotoxic agents and levels at percentile 30, compared to ies in long-term nonprogressors and influence on therapy outcome patients with CT genotype at percen- exposed but uninfected individuals (leukaemia with high P-gp levels has a tile 50 and CC genotype percentile 75 have shown that genetic factors play poor prognosis50), considerable efforts (Fellay et al, personal communication). an important role in determining the

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course of HIV infection. For example, Table 5 Adverse effects associated withantiretroviral drugs homozygosity for the CCR5-⌬32 deletion is associated with decreased Type of toxicity Clinical manifestations susceptibility to infection, while het- erozygosity is associated with delayed Mitochondrial toxicity Myopathy progression to disease.60–72 Recent Dilated cardiomyopathy studies have also shown that chemo- Peripheral neuropathy Hepatotoxicity kine receptor gene polymorphisms Pancreatitis 73–75 may affect response to HAART. Teratogenicity However, these effects were quite modest, and larger prospective studies Hypersensitivity Hypersensivity syndrome are required to confirm these initial Skin rashes Hepatitis findings, and to determine whether Pneumonitis they are related to individual drugs or Nephritis certain combinations. Relationships between polymorphisms in HLA, cyto- Lipodystrophy Fat accumulation kine, and chemokine genes and dis- Fat atrophy Hypertriglyceridaemia ease progression have also been ident- Insulin resistance 76 ified but whether they also Atherosclerotic arterial disease determine response to HAART has not Osteopenia been studied. The relationship between genes Miscellaneous Gastro-intestinal adverse effects Psychiatric manifestations determining disease progression and Nephrolithiasis drug response requires much further Haemorrhage study, and is likely to be increasingly Interactions important in the future. For example, the finding that HIV requires co-recep- Adapted from Carr and Cooper.82 tors such as chemokine receptors for entry into cells77 has led to the development of drugs that will antagonise TOXICITY OF ANTIRETROVIRALS as a goal by GlaxoSmithKline in order these receptors or prevent their Adverse effects associated with antire- to prevent hypersensitivity reactions expression.76 Their use and effective- trovirals are common, and can be div- to abacavir.85 Nevertheless, we are a ness will probably be increased by ided into several different categories long way from achieving this goal, and prior knowledge of the chemokine (Table 5). The whole area of adverse very little research has so far been car- receptor genotype. It is also possible effects in HIV disease has been ried out with toxicities associated that drug therapy may need to be indi- reviewed recently.81,82 This is an with antiretrovirals. vidualised on the basis of progressor increasingly important area given that As stated above, there are marked status, with those individuals classified the drugs, which have a narrow thera- inter-patient differences in plasma as being slow progressors receiving less peutic index, have to be used for long concentrations arising from the same potent therapy in order to avoid some periods, and are used in combinations drug regimen.4 For those adverse reac- of the toxic manifestations of the anti- that are liable to result in interactions. tions where a clear dose-response retrovirals. In order to reduce the Adverse effects to drugs are gene- relationship can be demonstrated, it emergence of resistant strains and pre- rally divided into dose-dependent can be hypothesised that patients who vent or minimise adverse effects of and dose-independent reactions.83 have low expression or deficiency of a antiretrovirals, studies are being per- Although this is an over-simplifi- particular metabolising enzyme will formed to examine the utility of struc- cation, since there is a dose-response achieve high plasma drug concen- tured treatment interruptions.76 Pre- relationship for most, if not all, trations and hence toxicity. Although liminary results have suggested that adverse reactions, it serves as a useful this has clearly been shown with non- structured treatment interruptions classification to discuss the role of gen- HIV drugs metabolised by polymor- may lead to immunologic control of etic susceptibility. Genetic factors phic enzymes such as CYP2D6,34 to viraemia in the absence of antiretrovi- probably play a role in predisposing to date no such studies have been perfor- ral therapy.78–80 Whether these effects all adverse reactions (although the med in HIV disease. With respect to show inter-individual variability and degree will vary),34 and one of the antiretrovirals, the CYP3A family may can be related to genetic determinants major goals of pharmacogenomics in be a fruitful area for research, since a is unknown, but opens up the the future will be to prevent adverse number of drugs metabolised by this intriguing possibility that treatment reactions by developing SNP profiles enzyme,28,86 commonly cause adverse interruptions could be individualised that are predictive of individual pre- effects that have been shown to be according to genotype. disposition.84 Indeed, this has been set dose-dependent. For example, with

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indinavir, drug crystallisation in urine classes of antiretroviral drugs.93 The now known to occur with NRTIs as and the formation of renal stones is a frequency of such reactions is rela- well,12 and indeed is probably the known adverse effect associated with tively high in comparison to the fre- result of a complex (as yet undeter- high indinavir plasma concen- quency seen in HIV-negative individ- mined pathogenesis) interaction trations.87 Although environmental uals with other drugs. Very little is between the disease, PIs and NRTIs, as factors such as hot climate are also known about the mechanisms of these well as host genetics. In HIV-negative important,82 the role of CYP3A4 and reactions, and indeed, their classi- patients, many of the lipodystrophies CYP3A5 polymorphisms needs to be fication as hypersensitivity reactions are thought to be inherited, although investigated, and may allow individu- implying that they are immune- these are much less common than the alisation of therapy at initiation so mediated, is based on the symptoma- LD observed in HIV-positive sub- that plasma levels are optimised to tology rather than specific laboratory jects.101 suppress viral replication, while at the evidence of an immune pathogenesis. The situation in HIV patients is com- same time avoiding urinary crystallis- No genetic studies have so far been plicated by the fact that: (a) lipodys- ation. A good relationship has also performed with the antiretrovirals trophy is not a single disease entity been shown between ritonavir and associated with hypersensitivity, and is probably a collection of overlap- neurological and gastro-intestinal although plans are underway to carry ping syndromes; and (b) there is no adverse effects.88 Clearly for both indi- out whole genome screening in good case definition.102 Thus, dissec- navir and ritonavir,30 the MDR1 poly- patients with and without abacavir tion of genetic predisposition is going morphism may also be important in hypersensitivity.85 Taking hypersensi- to be difficult. Nevertheless, using a determining plasma levels. A similar tivity reactions in non-HIV patients as case-control design, we have been able situation also exists with the NNRTI an illustration, it is likely that the gen- to show an association between the efavirenz, where high plasma levels etic predisposition is going to be poly- Ϫ238 promoter region TNF-␣ gene predict CNS side effects such as dizzi- genic,93 and genes involved in polymorphism (G→A), but not the ness, hallucinations, nightmares, and determining immune responsiveness Ϫ308 polymorphism, and lipodystro- psychiatric symptoms, while low lev- will play a more important role than phy.103 The TNF-␣ gene was chosen as els predict virological failure.89 It is those involved in determining drug a candidate gene because it is thought however more difficult to show the disposition. For example, hypersensi- to play a role in insulin resistance,104 same dose response relationship tivity to carbamazepine, an anticon- adipose tissue metabolism105 and between NRTIs and adverse effects, vulsant, has recently been shown to be viability106 and glucose homeo- since these drugs need to undergo con- associated with a promoter region stasis.107 Furthermore, this polymor- version intracellularly to their tri- polymorphism in the TNF-␣ gene and phism is thought to be functionally phosphate anabolites.27 HLA DR3,94 while the genes coding for active,108 although whether TNF-␣ The genetic basis of the mitochon- enzymes responsible for metabolism of secretion is increased or decreased in drial toxicities associated with the carbamazepine did not show an associ- adipose cells as a result of the G→A NRTIs is unclear. Given the similarity ation with hypersensitivity.95 substitution is not known. This should of these toxicities with rare mitochon- be regarded as the first step in the drial disorders,12 the mitochondrial Lipodystrophy genetic dissection of lipodystrophy genome is an obvious area of study. The syndrome of lipodystrophy or fat in HIV-positive patients since: However, any genetic predisposition re-distribution syndrome was first (a) replication of these results in an also needs to explain the tissue speci- reported about 3 years ago.96–100 This independent sample of patients is ficity of some of the adverse effects syndrome has caused a great deal of essential, and (b) identification of reported with the different drugs. concern, and is currently the subject of other genes in the overall pathogen- Thus, genes not encoded by the mito- intense research. It is characterised by esis of what is undoubtedly a poly- chondrial genome also need to be morphological abnormalities includ- genic predisposition will be needed. investigated. For example, adefovir is ing peripheral fat loss (in face, limbs associated with proximal renal tubular and buttocks) and fat accumulation EFFICACY AND TOXICITY OF toxicity, and this is thought to be due (in the abdomen, breast and dorso- DRUGS USED FOR to its selective accumulation within cervical spine). The syndrome is also OPPORTUNISTIC INFECTIONS the proximal tubular cells by the associated with metabolic abnormali- The use of drugs to treat opportunistic influx transporter OATP-1.90,91 Trans- ties such as dyslipidaemia and insulin infections (and their use for port of the NRTIs into the mitochon- resistance, which in some cases is prophylaxis) has declined since the dria is also likely to vary in a drug- and manifested as frank diabetes mellitus. advent of HAART.109,110 A large num- individual-specific manner and may In the long term, there are worries that ber of drugs are still used for opportun- be dependent on variation in the the syndrome may be associated with istic infections in HIV disease though, human mitochondrial deoxynucleo- the development of ischaemic heart and it is beyond the scope of this tide carrier.92 disease, cerebrovascular disease and review to cover all agents. Neverthe- Hypersensitivity reactions in HIV- osteopenia. The syndrome was less, it is important to be aware that positive patients are seen with all three initially reported with PIs, but it is both efficacy and toxicity of these

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compounds is subject to inter-individ- hydroxylamine metabolite) were not to unravel the complexity of HIV ual variability in pharmacokinetic and associated with susceptibility to SMX pharmacogenomics, a multi-pronged pharmacodynamic parameters. An hypersensitivity.121 Given the increas- approach is going to be needed. This example of a drug where genetic poly- ing laboratory evidence that SMX will need banking of DNA samples morphism is important for both effi- hypersensitivity is an immune- from on-going studies, and utilisation cacy and toxicity is isoniazid, which is mediated reaction,123–125 whether of archived samples, and subsequent used in the treatment of TB. Isoniazid polymorphisms in genes determining determination of the relationship undergoes N-acetylation by the poly- immune responsiveness are respon- between genotypes of candidate genes morphically expressed phase II sible for predisposition to SMX hyper- and response to therapy. Where a enzyme N-acetyltransferase type 2 sensitivity is unknown. particular relationship is identified in (NAT-2), which is deficient in 50% of retrospective studies, carefully Caucasians.111 The clearance of the CONCLUSIONS designed randomised prospective stud- drug is higher in fast acetylators than Improvement in HAART through the ies that incorporate not only measures in slow acetylators, and this may lead application of pharmacogenomics is of drug response, but also cost-effec- to therapeutic failure.111 By contrast, going to be a complex and difficult tiveness, will need to be performed. slow acetylators are more likely to process. The genomics of both the However, such prospective studies are develop adverse reactions such as per- virus and host will have to be con- unlikely to be possible when relatively ipheral neuropathy and SLE.112 sidered for successful application of rare adverse events are being studied. In HIV-negative patients, slow ace- genotypic guided therapy (Figure 1). Taken together with the fact that tylator phenotype and genotype have When one considers the virus, many of these adverse reactions are been shown to be risk factors for although a lot of mutations have been unpredictable and are likely to be hypersensitivity to sulphonamides.113–115 identified, the high capacity of the polygenic in predisposition, the In HIV patients, sulfamethoxazole virus to mutate means that many recruitment of large numbers of (SMX) is the most commonly used sul- more mutations or combinations of patients through multi-centre collab- phonamide, and is used for the treat- mutations will emerge, and much orations is going to be essential. Para- ment (in combination with work will need to be performed to doxically, this is probably going to be trimethoprim) of Pneumocystis carinii determine the phenotypic effect of the easier in HIV disease than in other pneumonia.116 SMX hypersensitivity mutation(s). Even less is known about conditions since the practice of multi- occurs at a frequency of between 30– how the genetic constitution of the centre international collaborations is 50% in HIV-positive patients, in com- host affects response to antiretrovirals, well practised in the many antiretrovi- parison to a frequency of 1–3% in HIV- although relevant studies are now ral drug studies that have been pub- negative patients.93,117 The mech- beginning to be conducted. It is also lished to date. It is also important to anism of toxicity is thought to involve important to note that when a genetic remember that even when an associ- metabolism of SMX to toxic determinant of efficacy is identified in ation between host genotype and drug hydroxylamine and nitroso metab- one ethnic population, it may not response may not institute changes in olites.118,119 It has thus been postu- necessarily be relevant in another eth- clinical practice in the short-term, it lated that slow acetylators may form nic population because of the some- may have other benefits. For example, increased amounts of the toxic metab- times-marked ethnic variations in the if a relationship between the MDR1 olites. Indeed, one study has shown frequency of polymorphisms. In order polymorphism and response to pro- that the slow acetylator phenotype is over-represented in SMX hypersensi- tive HIV-positive patients.120 However, no relationship was shown between the slow acetylator genotype and SMX hypersensitivity.121 The discordance between phenotype and genotype has been seen in HIV disease irrespective of whether patients were hypersensi- tive or not,122 and may reflect either problems with the phenotyping assay or that an unidentified factor in the sera of HIV-positive patients inhibits N-acetyltransferase. In addition to the studies with NAT-2, we have also shown that polymorphisms in the glu- tathione transferase genes (GSTM1, GSTT1 and GSTP1) and CYP2C9 Figure 1 Schematic representation of the many different factors that have to be con- (which metabolises SMX to the sidered in relation to the pharmacogenomics of HIV disease.

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tease inhibitors is demonstrated, this 8 Hogg RS, Heath KV, Yip B et al. Improved lescents, January 28, 2000 by the Panel on provides greater impetus and rationale survival among HIV-infected individuals fol- Clinical Practices for Treatment of HIV Infec- lowing initiation of antiretroviral therapy. tion. HIV Clin Trials 2000; 1:60–110. to developing Pgp inhibitors that can Jama-Journal of the American Medical Associ- 24 Velazquez-Campoy A, Todd MJ, Vega S, be used to modulate drug entry to the ation 1998; 279: 450–454. Freire E. Catalytic efficiency and vitality of sanctuary sites. The ultimate aim 9 Bartlett JA, DeMasi R, Quinn J, Moxham C, HIV-1 proteases from African viral subtypes. should be to develop an ‘HIV response Rousseau F. Overview of the effectiveness of Proc Natl Acad Sci USA 2001; 98: 6062– triple combination therapy in antiretroviral- 6067. chip’ that predicts the ideal drug com- naive HIV-1 infected adults. Aids 2001; 15: 25 Saag MS. HIV resistance testing in clinical bination to be used to maximise the 1369–1377. practice: a Qaly-fied success. Ann Intern response to the viral strain present, 10 Staszewski S, Miller V, Sabin C et al. Virolog- Med 2001; 134: 475–457. and prevent short- and long-term ical response to protease inhibitor therapy 26 Dunne AL, Mitchell FM, Coberly SK et al. in an HIV clinic cohort. Aids 1999; 13: Comparison of genotyping and phenotyp- adverse effects to a group of drugs that 367–373. ing methods for determining susceptibility have a relatively narrow therapeutic 11 Paterson DL, Swindells S, Mohr J et al. of HIV-1 to antiretroviral drugs. Aids 2001; index. Clearly, this is a goal that is Adherence to protease inhibitor therapy 15: 1471–1475. going to take a considerable length of and outcomes in patients with HIV infec- 27 Barry M, Mulcahy F, Back DJ. Antiretroviral tion. Ann Intern Med 2000; 133:21–30. time, but is nevertheless worth striv- therapy for patients with HIV disease. Br J 12 John M, Nolan D, Mallal S. Antiretroviral Clin Pharmacol 1998; 45: 221–228. ing for. therapy and the lipodystrophy syndrome. 28 Barry M, Mulcahy F, Merry C, Gibbons S, Antivir Ther 2001; 6:9–20. Back D. Pharmacokinetics and potential ACKNOWLEDGEMENTS 13 Deeks SG, Martin JN. Reassessing the goal interactions amongst antiretroviral agents of antiretroviral therapy in the heavily pre- We gratefully acknowledge the support of the used to treat patients with HIV infection. treated HIV-infected patient. Aids 2001; 15: MRC, Wellcome Trust, AVERT, and the Pharm- Clin Pharmacokinet 1999; 36: 289–304. 117–119. 29 Jones K, Bray PG, Khoo SH et al. P-glyco- aceutical Industry (GlaxoSmithKline, Bristol 14 Ramratnam B, Mittler JE, Zhang L et al. The protein and transporter MRP1 reduce HIV Myers Squibb, Merk Sharpe Dohme, Roche). decay of the latent reservoir of replication- protease inhibitor uptake in CD4 cells: competent HIV-1 is inversely correlated potential for accelerated viral drug resist- DUALITY OF INTEREST with the extent of residual viral replication ance? Aids 2001; 15: 1353–1358. during prolonged anti-retroviral therapy. None declared. 30 Kim RB, Fromm MF, Wandel C et al. The Nat Med 2000; 6:82–85. drug transporter P-glycoprotein limits oral 15 Richman DD. HIV chemotherapy. Nature absorption and brain entry of HIV-1 pro- Correspondence should be sent to 2001; 410: 995–1001. tease inhibitors. J Clin Invest 1998; 101: M Pirmohamed, Department of 16 Montaner JS, Mellors JW. Antiretroviral ther- 289–294. Pharmacology and Therapeutics, The apy for previously treated patients. N Engl J 31 Ingelman-Sundberg M. Implications of University of Liverpool, Ashton Street, Med 2001; 345: 452–455. polymorphic cytochrome p450-dependent 17 Durant J, Clevenbergh P, Garraffo R et al. Liverpool, L69 3GE, UK. drug metabolism for drug development. Importance of protease inhibitor plasma Tel ϩ44 151 794 5549 Drug Metab Dispos 2001; 29(4 Pt 2): levels in HIV-infected patients treated with Fax: ϩ44 151 794 5540 570–573. genotypic-guided therapy: pharmacologi- Ȱ 32 Gonzalez F, Meyer UA. Molecular genetics E-mail: munirp liv.ac.uk cal data from the Viradapt Study. Aids of the debrisoquin-sparteine polymor- 2000; 14: 1333–1339. phism. Clin Pharmacol Ther 1991; 50: 18 Clevenbergh P, Durant J, Halfon P et al. Per- REFERENCES 233–238. sisting long-term benefit of genotype- 1 Gottlieb MS. AIDS—past and future. N Engl 33 Ingelman-Sundberg M, Oscarson M, J Med 2001; 344: 1788–1791. guided treatment for HIV- infected patients McLellan RA. Polymorphic human cyto- 2 Palella FJ, Delaney KM, Moorman AC et al. failing HAART. The Viradapt Study: week 48 chrome P450 enzymes: an opportunity for Declining morbidity and mortality among follow-up. Antivir Ther 2000; 5:65–70. individualized drug treatment. Trends Phar- patients with advanced human immuno- 19 Harrigan PR, Hertogs K, Verbiest W et al. macol Sci 1999; 20: 342–349. deficiency virus infection. HIV Outpatient Baseline HIV drug resistance profile predicts 34 Pirmohamed M, Park BK. Genetic suscepti- Study Investigators. N Engl J Med 1998; response to ritonavir-saquinavir protease bility to adverse drug reactions. Trends 338: 853–860. inhibitor therapy in a community setting. Pharmacol Sci 2001; 22: 298–305. 3 Roses AD. Pharmacogenetics and the prac- Aids 1999; 13: 1863–1871. tice of medicine. Nature 2000; 405: 857– 20 Zolopa AR, Shafer RW, Warford A et al. HIV- 35 Goldstein JA. Clinical relevance of polymor- 865. 1 genotypic resistance patterns predict phisms in the human CYP2C subfamily. Br 4 Back DJ, Khoo SH, Gibbons SE, Merry C. response to saquinavir- ritonavir therapy in J Clin Pharmacol 2001; 52: 349–356. The role of therapeutic drug monitoring in patients in whom previous protease inhibi- 36 Thummel KE, Wilkinson GR. In vitro and in treatment of HIV infection. Br J Clin Pharma- tor therapy had failed. Ann Intern Med vivo drug interactions involving human col 2001; 51: 301–308. 1999; 131: 813–821. CYP3A. Annu Rev Pharmacol Toxicol 1998; 5 Carpenter CC, Cooper DA, Fischl MA et al. 21 Baxter JD, Mayers DL, Wentworth DN et al. 38: 389–430. Antiretroviral therapy in adults: updated A randomized study of antiretroviral man- 37 Gellner K, Eiselt R, Hustert E et al. Genomic recommendations of the International AIDS agement based on plasma genotypic anti- organization of the human CYP3A locus: Society—USA Panel. Jama 2000; 283: retroviral resistance testing in patients fail- identification of a new, inducible CYP3A 381–390. ing therapy. CPCRA 046 Study Team for the gene. Pharmacogenetics 2001; 11: 111– 6 Ledergerber B, Egger M, Opravil M et al. Terry Beirn Community Programs for Clini- 121. Clinical progression and virological failure cal Research on AIDS. Aids 2000; 14: F83– 38 Kuehl P, Zhang J, Lin Y et al. Sequence on highly active antiretroviral therapy in F93. diversity in CYP3A promoters and charac- HIV-1 patients: a prospective cohort study. 22 Weinstein MC, Goldie SJ, Losina E et al. Use terization of the genetic basis of polymor- Swiss HIV Cohort Study. Lancet 1999; 353: of genotypic resistance testing to guide HIV phic CYP3A5 expression. Nat Genet 2001; 863–868. therapy: clinical impact and cost-effective- 27: 383–391. 7 Mocroft A, Katlama C, Johnson AM et al. ness. Ann Intern Med 2001; 134: 440–450. 39 Bertilsson G, Heidrich J, Svensson K et al. AIDS across Europe, 1994–98: the EuroSIDA 23 Guidelines for the Use of Antiretroviral Identification of a human nuclear receptor study. Lancet 2000; 356: 291–296. Agents in HIV-Infected Adults and Ado- defines a new signaling pathway for CYP3A

www.nature.com/tpj HIV pharmacogenomics M Pirmohamed and DJ Back 252

induction. Proc Natl Acad Sci USA 1998; 95: The C3435T mutation in the human MDR1 ance to HIV-1 infection in Caucasian indi- 12208–12213. gene is associated with altered efflux of the viduals bearing mutant alleles of the CCR- 40 Kliewer SA, Moore JT, Wade L et al.An P-glycoprotein substrate rhodamine 123 5 chemokine receptor gene. Nature 1996; orphan nuclear receptor activated by pre- from CD56ϩ natural killer cells. Pharmaco- 382: 722–725. gnanes defines a novel steroid signaling genetics 2001; 11: 293–298. 67 Hoffman TL, MacGregor RR, Burger H, Mick pathway. Cell 1998; 92:73–82. 54 Tanabe M, Ieiri I, Nagata N et al. Expression R, Doms RW, Collman RG. CCR5 genotypes 41 Lehmann JM, McKee DD, Watson MA, Will- of P-glycoprotein in human placenta: in sexually active couples discordant for son TM, Moore JT, Kliewer SA. The human relation to genetic polymorphism of the human immunodeficiency virus type 1 orphan nuclear receptor PXR is activated by multidrug resistance (MDR)-1 gene. J Phar- infection status. J Infect Dis 1997; 176: compounds that regulate CYP3A4 gene macol Exp Ther 2001; 297: 1137–1143. 1093–1096. expression and cause drug interactions. J 55 Cascorbi I, Gerloff T, Johne A et al. Fre- 68 Smith MW, Dean M, Carrington M, Huttley Clin Invest 1998; 102: 1016–1023. quency of single nucleotide polymorphisms GA, O’Brien SJ. CCR5-delta 32 gene 42 Zhang J, Kuehl P, Green ED et al. The in the P-glycoprotein drug transporter deletion in HIV-1 infected patients. Lancet human pregnane X receptor: genomic MDR1 gene in white subjects. Clin Pharma- 1997; 350: 741; discussion 742. structure and identification and functional col Ther 2001; 69: 169–174. 69 Smith MW, Dean M, Carrington M et al. characterization of natural allelic variants. 56 Fellay J, Marzolini J, Back DJ et al. Predictive Contrasting genetic influence of CCR2 and Pharmacogenetics 2001; 11: 555–572. power of P-glycoprotein and CYP2D6 poly- CCR5 variants on HIV-1 infection and dis- 43 Wandel C, Witte JS, Hall JM, Stein CM, morphisms for plasma levels of antiretrovi- ease progression. Hemophilia Growth and Wood AJ, Wilkinson GR. CYP3A activity in ral agents. 8th Conference on Retroviruses Development Study (HGDS), Multicenter African American and European American and Opportunistic Infections, Chicago IL USA AIDS Cohort Study (MACS), Multicenter men: population differences and functional 2001: Abstract No. 260. Hemophilia Cohort Study (MHCS), San effect of the CYP3A4*1B5Ј- promoter 57 Ameyaw MM, Regateiro F, Li T et al. MDR1 Francisco City Cohort (SFCC), ALIVE Study. region polymorphism. Clin Pharmacol Ther pharmacogenetics: frequency of the Science 1997; 277: 959–965. 2000; 68:82–91. C3435T mutation in exon 26 is significantly 70 McNicholl JM, Smith DK, Qari SH, Hodge 44 Mackenzie PI, Miners JO, McKinnon RA. influenced by ethnicity. Pharmacogenetics T. Host genes and HIV: the role of the Polymorphisms in UDP glucuronosyl- 2001; 11: 217–221. chemokine receptor gene CCR5 and its transferase genes: functional consequences 58 Schaeffeler E, Eichelbaum M, Brinkmann U allele. Emerg Infect Dis 1997; 3: 261–271. and clinical relevance. Clin Chem Lab Med et al. Frequency of C3435T polymorphism 71 Smith O. HIV CCR5 resistance incomplete. 2000; 38: 889–892. of MDR1 gene in African people. Lancet Nat Med 1997; 3: 372–373. 45 Lee CG, Gottesman MM, Cardarelli CO et 2001; 358: 383–384. 72 Martin MP, Dean M, Smith MW et al. Gen- al. HIV-1 protease inhibitors are substrates 59 Meaden ER, Hoggard PG, Newton P et al. etic acceleration of AIDS progression by a for the MDR1 multidrug transporter. Bio- P-glycoprotein and MRP1 expression and promoter variant of CCR5. Science 1998; chemistry 1998; 37: 3594–3601. reduced ritonavir and saquinavir accumu- 282: 1907–1911. 46 Washington CB, Wiltshire HR, Man M et al. lation in vivo. Clin Pharmacol Therapeut 73 O’Brien TR, McDermott DH, Ioannidis JP et The disposition of saquinavir in normal and 2001; (submitted). al. Effect of chemokine receptor gene poly- P-glycoprotein deficient mice, rats, and in 60 Martin MP, Carrington M, Dean M et al. morphisms on the response to potent anti- cultured cells. Drug Metab Dispos 2000; 28: CXCR4 polymorphisms and HIV-1 patho- retroviral therapy. Aids 2000; 14: 821–826. 1058–1062. genesis. J Acquir Immune Defic Syndr Hum 74 Guerin S, Meyer L, Theodorou I et al. CCR5 47 Huisman MT, Smit JW, Schinkel AH. Sig- Retrovirol 1998; 19: 430. delta32 deletion and response to highly nificance of P-glycoprotein for the pharma- 61 Kostrikis LG, Neumann AU, Thomson B et active antiretroviral therapy in HIV-1- cology and clinical use of HIV protease al. A polymorphism in the regulatory region infected patients. Aids 2000; 14: 2788– inhibitors. Aids 2000; 14: 237–242. of the CC-chemokine receptor 5 gene 2790. 48 Kerb R, Hoffmeyer S, Brinkmann U. ABC influences perinatal transmission of human 75 Valdez H, Purvis SF, Lederman MM, Fill- drug transporters: hereditary polymor- immunodeficiency virus type 1 to African- ingame M, Zimmerman PA. Association of phisms and pharmacological impact in American infants. J Virol 1999; 73: 10264– the CCR5delta32 mutation with improved MDR1, MRP1 and MRP2. Pharmacogenom- 10271. response to antiretroviral therapy. Jama ics 2001; 2:51–64. 62 Dean M, Carrington M, Winkler C et al. 1999; 282: 734. 49 Brinkmann U, Roots I, Eichelbaum M. Phar- Genetic restriction of HIV-1 infection and 76 Hogan CM, Hammer SM. Host determi- macogenetics of the human drug-trans- progression to AIDS by a deletion allele of nants in HIV infection and disease. Part 2: porter gene MDR1: impact of polymor- the CKR5 structural gene. Hemophilia genetic factors and implications for antire- phisms on pharmacotherapy. Drug Discov Growth and Development Study, Multicen- troviral therapeutics. Ann Intern Med 2001; Today 2001; 6: 835–839. ter AIDS Cohort Study, Multicenter Hemo- 134: 978–996. 50 Dhooge C, De Moerloose B, Laureys G et philia Cohort Study, San Francisco City 77 Dragic T, Litwin V, Allaway GP et al. HIV-1 al. P-glycoprotein is an independent prog- Cohort, ALIVE Study. Science 1996; 273: entry into CD4ϩ cells is mediated by the nostic factor predicting relapse in child- 1856–1862. chemokine receptor CC- CKR-5. Nature hood acute lymphoblastic leukaemia: 63 Liu R, Paxton WA, Choe S et al. Homo- 1996; 381: 667–673. results of a 6-year prospective study. Br J zygous defect in HIV-1 coreceptor accounts 78 Ruiz L, Martinez-Picado J, Romeu J et al. Haematol 1999; 105: 676–683. for resistance of some multiply-exposed Structured treatment interruption in chron- 51 Mickley LA, Lee JS, Weng Z et al. Genetic individuals to HIV-1 infection. Cell 1996; 86: ically HIV-1 infected patients after long- polymorphism in MDR-1: a tool for examin- 367–377. term viral suppression. Aids 2000; 14: ing allelic expression in normal cells, 64 Huang Y, Paxton WA, Wolinsky SM et al. 397–403. unselected and drug-selected cell lines, and The role of a mutant CCR5 allele in HIV-1 79 Miller V, Sabin C, Hertogs K et al. Virolog- human tumors. Blood 1998; 91: 1749– transmission and disease progression. Nat ical and immunological effects of treatment 1756. Med 1996; 2: 1240–1243. interruptions in HIV-1 infected patients with 52 Hoffmeyer S, Burk O, von Richter O et al. 65 Zimmerman PA, Buckler-White A, Alkhatib treatment failure. Aids 2000; 14: 2857– Functional polymorphisms of the human G et al. Inherited resistance to HIV-1 con- 2867. multidrug-resistance gene: multiple ferred by an inactivating mutation in CC 80 Izopet J, Massip P, Souyris C et al. Shift in sequence variations and correlation of one chemokine receptor 5: studies in popu- HIV resistance genotype after treatment allele with P-glycoprotein expression and lations with contrasting clinical pheno- interruption and short-term antiviral effect activity in vivo. Proc Natl Acad Sci USA 2000; types, defined racial background, and following a new salvage regimen. Aids 97: 3473–3478. quantified risk. Mol Med 1997; 3:23–36. 2000; 14: 2247–2255. 53 Hitzl M, Drescher S, van der Kuip H et al. 66 Samson M, Libert F, Doranz BJ et al. Resist- 81 Max B, Sherer R. Management of the

The Pharmacogenomics Journal HIV pharmacogenomics M Pirmohamed and DJ Back 253

adverse effects of antiretroviral therapy and 98 Viraben R, Aquilina C. Indinavir-associa- drome. Pharmacogenetics 1995; 5: medication adherence. Clin Infect Dis 2000; ted lipodystrophy. AIDS 1998; 12: F37– 255–258. 30 Suppl 2: S96–116. F39. 114 Rieder MJ, Shear NH, Kanee A, Tang BK, 82 Carr A, Cooper DA. Adverse effects of anti- 99 Carr A, Samaras K, Burton S et al. A syn- Spielberg SP. Prominence of slow acetyl- retroviral therapy. Lancet 2000; 356: drome of peripheral lipodystrophy, hyp- ator phenotype among patients with sul- 1423–1430. erlipidaemia and insulin resistance in fonamide hypersensitivity reactions. Clin 83 Pirmohamed M, Breckenridge AM, Kitter- patients receiving HIV protease inhibi- Pharmacol Ther 1991; 49:13–17. ingham NR, Park BK. Adverse drug reac- tors. AIDS 1998; 12: F51–F58. 115 Zielinska E, Niewiarowski W, Bodalski J. tions. BMJ 1998; 316: 1295–1298. 100 Miller KK, Daly PA, Sentochnik D et al. The arylamine N-acetyltransferase 84 Roses AD. Pharmacogenetics and future Pseudo-Cushing’s syndrome in human (NAT2) polymorphism and the risk of drug development and delivery. Lancet immunodeficiency virus-infected adverse reactions to co-trimoxazole in 2000; 355: 1358–1361. patients. Clin Infect Dis 1998; 27:68–72. children. Eur J Clin Pharmacol 1998; 54: 85 Black R. GSK bets on the genomic route to 101 Flier JS. Pushing the envelope on lipodys- 779–785. trophy. Nat Genet 2000; 24: 103–104. 116 Smith GH. Treatment of infections in the drug safety. Inpharma 2001; 1280:3–4. 102 Safrin S, Grunfeld C. Fat distribution and patient with acquired immunodeficiency 86 Barry M, Gibbons S, Back D, Mulcahy F. metabolic changes in patients with HIV syndrome. Arch Intern Med 1994; 154: Protease inhibitors in patients with HIV dis- infection. Aids 1999; 13: 2493–2505. 949–973. ease—Clinically important pharmacokinetic 103 Maher B, Alfirevic A, Vilar J, Wilkins E, 117 Carr A, Cooper DA. Pathogenesis and considerations. Clin Pharmacokinet 1997; Park BK, Pirmohamed M. Tumour management of HIV-associated drug 32: 194–209. necrosis factor-alpha promoter region hypersensitivity. AIDS Clin Rev 1995; 96: 87 Salahuddin S, Hsu YS, Bucholz NP, Diele- gene polymorphisms in patients with 65–97. man JP, Gyssens IC, Kok DJ. Is indinavir crys- HIV-1 associated lipodystrophy. XIII Inter- 118 Naisbitt DJ, O’Neill PM, Pirmohamed M, talluria an indicator for indinavir stone for- national AIDS Conference July 9–14, Park BK. Synthesis and reactions of mation? AIDS 2001; 15: 1079–1080. 2000: Abstract LbPp113. nitroso sulfamethoxazole with biological 88 Gatti G, Di Biagio A, Casazza R et al. The 104 Qi C, Pekala PH. Tumor necrosis factor- nucleophiles—implications for immune- relationship between ritonavir plasma levels alpha-induced insulin resistance in adipo- mediated toxicity. Bioorg Med Chem Let and side-effects: implications for thera- cytes. Proc Soc Exp Biol Med 2000; 223: 1996; 6: 1511–1516. peutic drug monitoring. Aids 1999; 13: 128–135. 119 Naisbitt DJ, Hough SJ, Gill HJ, Pirmo- 2083–2089. 105 Sethi JK, Hotamisligil GS. The role of TNF hamed M, Kitteringham NR, Park BK. 89 Marzolini C, Telenti A, Decosterd LA, Greub alpha in adipocyte metabolism. Semin Cellular disposition of sulphamethox- G, Biollaz J, Buclin T. Efavirenz plasma levels Cell Dev Biol 1999; 10:19–29. azole and its metabolites: implications for can predict treatment failure and central 106 Prins JB, Niesler CU, Winterford CM et al. hypersensitivity. Br J Pharmacol 1999; nervous system side effects in HIV-1- Tumor necrosis factor-alpha induces 126: 1393–1407. infected patients. Aids 2001; 15:71–75. apoptosis of human adipose cells. Dia- 120 Carr A, Gross AS, Hoskins JM, Penny R, 90 Cihlar T, Lin DC, Pritchard JB, Fuller MD, betes 1997; 46: 1939–1944. Cooper DA. Acetylation phenotype and Mendel DB, Sweet DH. The antiviral nucleo- 107 Jovinge S, Hamsten A, Tornvall P et al. cutaneous hypersensitivity to trimetho- tide analogs cidofovir and adefovir are Evidence for a role of tumor necrosis fac- prim-sulphamethoxazole in HIV-infected novel substrates for human and rat renal tor alpha in disturbances of triglyceride patients. AIDS 1994; 8: 333–337. organic anion transporter 1. Mol Pharmacol and glucose metabolism predisposing to 121 Pirmohamed M, Alfirevic A, Vilar J et al. 1999; 56: 570–580. coronary heart disease. Metabolism 1998; Association analysis of drug metabolizing 91 Cihlar T, Ho ES, Lin DC, Mulato AS. Human 47: 113–118. enzyme gene polymorphisms in HIV- renal organic anion transporter 1 (hOAT1) 108 Molvig J, Baek L, Christensen P et al. positive patients with co-trimoxazole and its role in the nephrotoxicity of antiviral Endotoxin-stimulated human monocyte hypersensitivity. Pharmacogenetics 2000; nucleotide analogs. Nucleosides Nucleotides secretion of interleukin-1, tumor necrosis 10: 705–713. factor-alpha, and prostaglandin-e2 122 O’Neil WM, Drobitch RK, MacArthur RD Nucleic Acids 2001; 20: 641–648. shows stable interindividual differences. et al. Acetylator phenotype and geno- 92 Dolce V, Fiermonte G, Runswick MJ, Palmi- Scan J Immunol 1988; 27: 705–716. type in patients infected with HIV: discor- eri F, Walker JE. The human mitochondrial 109 Ledergerber B, Mocroft A, Reiss P et al. dance between methods for phenotype deoxynucleotide carrier and its role in the Discontinuation of secondary prophy- determination and genotype. Pharmaco- toxicity of nucleoside antivirals. Proc Natl laxis against Pneumocystis carinii pneu- genetics 2000; 10: 171–182. Acad Sci USA 2001; 98: 2284–2288. monia in patients with HIV infection who 123 Schnyder B, Burkhart C, Schnyder-Frutig 93 Pirmohamed M, Park BK. HIV and drug have a response to antiretroviral therapy. K et al. Recognition of sulfamethoxazole allergy. Curr Opin Allergy Clin Immunol Eight European Study Groups. N Engl J and its reactive metabolites by drug-spe- 2001; 1: 311–316. Med 2001; 344: 168–174. cific CD4ϩ T cells from allergic individ- 94 Pirmohamed M, Lin K, Chadwick D, Park 110 Weverling GJ, Mocroft A, Ledergerber B uals. J Immunol 2000; 164: 6647–6654. BK. TNFalpha promoter region gene poly- et al. Discontinuation of Pneumocystis 124 Naisbitt DJ, Gordon SF, Pirmohamed M, morphisms in carbamazepine-hypersensi- carinii pneumonia prophylaxis after start Park BK. Immunological principles of tive patients. Neurology 2001; 56: 890–896. of highly active antiretroviral therapy in adverse drug reactions: the initiation and 95 Leeder JS. Mechanisms of idiosyncratic HIV-1 infection. EuroSIDA Study Group. propagation of immune responses elic- hypersensitivity reactions to antiepileptic Lancet 1999; 353: 1293–1298. ited by drug treatment. Drug Saf 2000; drugs. Epilepsia 1998; 39(Suppl 7):S8– 111 Price Evans DA. N acetyltransferase. Phar- 23: 483–507. S16. macol Ther 1989; 42: 157–234. 125 Naisbitt DJ, Gordon SF, Pirmohamed M 96 Lo JC, Mulligan K, Tai VW, Algren H, 112 Park BK, Pirmohamed M, Kitteringham et al. Antigenicity and immunogenicity of Schambelan M. ‘Buffalo hump’ in men with NR. Idiosyncratic drug reactions: a mech- sulphamethoxazole: demonstration of HIV-1 infection. Lancet 1998; 351: 867– anistic evaluation of risk factors. Br J Clin metabolism-dependent haptenation and 870. Pharmacol 1992; 34: 377–395. T-cell proliferation in vivo. Br J Pharmacol 97 Miller KD, Jones E, Yanovski JA, Shankar R, 113 Wolkenstein P, Carriere V, Charue D et al. 2001; 133: 295–305. Feuerstein I, Falloon J. Visceral abdominal- A slow acetylator genotype is a risk factor fat accumulation associated with the use of for sulfonamide-induced toxic epidermal indinavir. Lancet 1998; 351: 871–875. necrolysis and Stevens-Johnson syn-