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The availability of effective combination antiretroviral therapy since 1995 has changed the prognosis of HIV disease dramatically. Five drug classes are currently in use: nucleoside analogs (NRTI), nucleotide analogs (NtRTI), non-nucleoside inhibitors of the HIV reverse transcriptase (NNRTI), inhibitors of the HIV protease (PI), and peptidic inhibitors of the viral-cell fusion process. PIs are moderate to strong inhibitors of various cytochrome P450 (CYP450) isoenzymes (Table 2), whereas NNRTIs are inducers of several CYP450 isoenzymes. In addition, PIs are substrates of the multidrug transporter P-glycoprotein (P-gp). There is marked interindividual variation in plasma drug levels, in efficacy, and in susceptibility to adverse reactions (6-8). Antiretroviral agents, in particular NNRTIs and PIs, are subject to significant drug-drug interactions within combination antiretroviral therapy and with medications used to treat opportunistic diseases associated with AIDS (e.g., anti-mycobacterial drugs). In addition, the disease itself can affect enzymatic activity. For example, patients with AIDS and acute infections have altered patterns of enzymatic drug metabolism (9). Using caffeine as a probe for NAT2 enzymatic activity, we identified an increased number of slow acetylators in AIDS patients with an acute infection, compared with the control healthy volunteers and HIV-asymptomatic patients. The patterns of oxidative metabolism (decreased demethylation, increased 8-hydroxylation) were also altered. This type of phenomenon might contribute to the increased incidence of adverse reactions observed in these patients, a phenomenon similar to that described in the treatment of TB (10-12).

Irrespective of these considerations, polymorphisms in genes encoding for metabolizing enzymes, carrier proteins, and drug transporters are expected to influence antiretro-viral plasma drug levels, bound and free, and also intracompartmental and intracellular effective levels (Fig. 2). These three components and their relevance in the treatment of HIV diseases are discussed in the following sections.

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Pharmacogenetic determinants

Table 2 Inherited Differences in the Metabolism, Transport and Disposition, and Toxicity of Anti-infective Drugs

Gene/protein

Anti-infective drug

Polymorphism/mutation

Consequence

Phase I enzymesa CYP3A

CYP2C19

Other CYP: CYP2D6, CYP2C9, CYP2E1, CYP1A2, CYP2B6

Phase II enzymes jV-acetyltransferase (NAT) II

Glucose 6-phosphate dehydrogenase (G6PD) Thiopurine

S-methyltransferase (:TPMT)

Rifampicin, ceftriaxone, erythromycin, clarithromycin, HIV protease inhibitors Amoxicillin, clarithromycin, (plus proton pump inhibitors: omeprazole/ lansoprazole/rabeprazole), ketoconazole, HIV protease inhibitors, rifampicin, isoniazid HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, erythromycin, isoniazid, rifampin

Isoniazid, sulfonamides, dapsone

Primaquine, dapsone, sulfonamides

Moxalactam, cephalosporins

Role of polymorphisms in CYP3A4 unclear. CYP3A5*! express high amounts of CYP3A5 CYP2C19 PM, heterozygous/ extensive metabolizer

All enzymes have variant alleles associated with PM

Slow acetylators G6PD deficiency TPMT deficiency

Interindividual variation in 20% of the bioavailability of substrates CYP2C19 PM better cure rates; EM less eradication of H. pylori; PM implicated in adverse drug reactions

Interindividual variation in drug levels and increased adverse drug reactions

Neuropathy, hematologic toxicities Hemolysis

Hematopoietic toxicity— bleeding

('Continued)

Table 2 Inherited Differences in the Metabolism, Transport and Disposition, and Toxicity of Anti-infective Drugs (Continued)

Gene/protein

Anti-infective drug

Polymorphism / mutation

Consequence

Transporters P-glycoprotein (MDR1)

Multidrug resistance-related protein 1 (MRP1, ABCCl)

MRP2 (ABCC2)

MRP4 (ABCC4)

MRP5 (ABCC5)

OAT1 (SLC22A6) OAT2 (SLC22A7)

HIV protease inhibitors, rifampicin, ceftriaxone, erythromycin, clarithromycin, antifungals (ketoconazole, Itraconazole, amphotericin B), chloroquine, quinine

Fluoroquinolones, tetracyclines, macrolides, LTC4 inhibitors (penicillin, probenecid, rifampicin, clotrimazole) Substrates: fluoroquinolones, tetracyclines, macrolides, HIV protease inhibitors, penicillin sulfinpyrazone, LTC4 inhibitors: HIV protease inhibitors, cefodizime rifampicin Adefovir, azidothymidine, lamivudine, ddC, stavudine Adefovir, azidothymidine, lamivudine, ddC, stavudine Cephalosporins, adefovir, cidofovir Azidothymidine

Exon 21 and exon 26 polymorphism

Arg433Ser

Dubin-Johnson syndrome-related nonsynonymous mutations

Multiple Multiple

Drug levels of protease inhibitors, intracellular drug concentration, immune recovery in HIV-infected individuals

Reduced intracellular drug concentration, reduced body clearance?

Reduced bilirubin efflux

Unknown Unknown n.i. n.i.

0CT1 (SLC22A1) Azidothymidine ArgôlCys

Inhibitors: indinavir, saquinavir, Cys88Arg ritonavir, nefinavir Gly401Ser

0CT2

OATP-C (SLC21A6)

0ATP8 (SLC21A8)

OATP-B (SLC21A9) Other

Mitochondrial ribosomal 12S rRNA gene

HLA haplotypes

Organic cations

Benzylpenicillin, rifampicin Inhibitor: rifamycin, LTC4

Rifampicin Inhibitor: rifamycin Amphiphilic organic anions

Aminoglycoside antibiotics (streptomycin)

Hepatitis B vaccine abacavir

P54S, M165I, R400C, K432Q, insertion Phe73Ala (*2 allele)

Val82Ala and Glul56Gly (*3 allele)

A1555G and T961C mutation of 12SrRNA gene

Many haplotypes are involved: haplotype HLA-B*5701, HLA-DR7, HLA-DQ3

Reduced in vitro uptake, reduced hepatic clearance/intestinal absorption, increased susceptibility to drug-drug interaction Reduced in vitro uptake, nonfunctional protein Reduced in vitro uptake, reduced hepatic drug clearance?

Reduced in vitro uptake

Irreversible deafness in maternally inherited mitochondrial mutations Poor and nonresponse to hepatitis B vaccine Hypersensitivity reaction to abacavir aSee www.imm.ki.se/CYPalleles/for detailed description of CYP alleles and SNPs.

Abbreviations', n.i., none identified; PM, poor metabolizer; EM, extensive metabolizer; LTC4, leukotriene C4; TPMT, thiopurine S-methyltransferase.

Figure 2 Schematic representation of known determinants of intracellular drug concentration of antiretroviral agents.

CYP450 Metabolism

PIs and NNRTIs, unlike NRTIs, are extensively metabolized by CYPP450 isozymes present in the liver and in the gut wall, with CYP3A being the most important isozyme: other isozymes, such as CYP2C9, CYP2C19, CYP2D6, and CYP2B6, also contribute (13-16). Most PIs are inhibitors of CYP3A, with ritonavir being the most potent and saquinavir the least (17,18). Because some PIs simultaneously inhibit and/or induce these enzymatic systems, whereas NNRTIs act as inducers, regimens combining PIs with each other or with NNRTIs are complicated by influences from both classes of drugs. In addition, and as described previously, the disease status may also modulate the enzymatic activity of CYP450. In a study addressing this question, the genotype and phenotype of CYP2D6 were investigated in 61 HIV-infected and AIDS patients. The authors found an apparent shift towards the poor metabolizer (PM) phenotype from the extensive metabolizer (EM) genotype. The authors concluded that a change might occur in HIV-positive patients such that their CYP2D6 activity approaches that of the PMs, despite having an EM genotype (19).

Fellay et al. (20) conducted a pilot study on 123 HIV-infected patients to analyze the association of CYP polymorphims and plasma drug levels and response. Investigation included CYP3A4*1B and *2 (21), CYP3A5*1, CYP2D6 *3, *4, and *6, and gene duplication (22-24) and CYP2C19 exons 4 and 9 polymorphisms and also the functional analysis of CYP3A (midazolam to 1'-hydroxymidazolam oxidation). Patients who were either homozygous or heterozygous at one CYP2D6 allele associated with a PM phenotype had higher median plasma nelfinavir levels than patients with a CYP2D6 EM genotype. In contrast, there was no significant contribution of CYP2C19 genotype to nelfinavir plasma drug levels, despite the fact that in vitro data identify CYP2C19 as the main P450 isoform involved in the metabolism of nelfinavir (25,26). Functional and genetic analysis of CYP3A alleles did not identify an association with drug levels in vivo. Virological and immunological responses to treatment did not vary among patients with the various CYP alleles (20). A detailed description of CYP alleles and single nucleotide polymorphisms is beyond the scope of this chapter; please refer to (27) for precise nomenclature and functional consequences.

P-gp

The MDR1gene codes for P-gp, which is an ABC transporter. PIs are substrates (as well as inhibitors and/or inducers) of this transporter. The intracellular accumulation and active transport of PIs have been studied by Jones et al. (28,29). The recent identification of polymorphisms in the MDR1 gene associated with changes in transporter function spurred a significant amount of research, including in the field of HIV. The current state of knowledge has been reviewed recently by Kim (30), and there appears to be considerable confusion and controversy (Table 3). Hoffmeyer et al. (31) characterized the MDR1 gene in a group of Caucasian subjects. They reported that individuals homozygous for the MDR1 exon 26 3435T allele had significantly decreased intestinal P-gp expression and increased digoxin plasma concentrations after oral administration. In contrast, Sakaeda et al. (32) showed that digoxin plasma levels were lower in Japanese subjects carrying the 3435T allele. Nakanuma also found lower digoxin plasma levels for TT subjects, albeit with a higher MDR1 expression (33). Kim et al. (34) reported that the 3435T/T genotype was associated with high expression in vitro and low plasma concentrations of fexofenadine, a model substrate drug for the P-gp transporter. In a study investigating MDR1 tissue expression, Goto et al. (35) reported that the 3435C/T polymorphism in exon 26 did not significantly alter the MDR1 level expressed in intestinal enterocytes or correlate with the tacrolimus concentration /dose ratio. In our study, with a cohort of HIV-infected patients, the 3435TT genotype was associated with lower expression of P-gp (both MDR1 mRNA and P-gp levels) in peripheral-blood mononuclear cells, and lower plasma concentrations of nelfinavir and efavir-enz, as compared with the 3435CC genotype (20). This synonymous 3435T polymorphism is linked to the nonsynonymous exon 21 2677G/T (Ala893Ser) polymorphism. Therefore, the possibility exists that some of the observed differences in P-gp activity attributed to the 3435C/T polymorphism may reflect the exon 21 polymorphism and its effects on transporter activity. Several studies have compared the effects of 2677G/T SNP on P-gp activity. However, the results obtained so far have been variable and conflicting (Table 3), and thus recent activity has shifted towards determining the role of MDR1 haplotypes on the functional activity of the protein product.

Many of the drugs that are transported by P-gp are also metabolized by the cytochrome P450 enzymes, especially CYP3A. It is likely that because P-gp can influence the intracellular concentration of many CYP3A substrates it can also affect the availability of those substrates to CYP3A and therefore the extent of their metabolism. P-gp thus plays an important role in modulating the expression of CYP3A and is likely to complicate the predictability of drug interactions among drugs that are substrates for both P-gp and CYP3A systems (33). It has been reported that carriers of the 3435T allele have reduced expression of intestinal CYP3A4 mRNA (35). It is not clear, however, how a synonymous SNP in MDR1 can alter CYP3A4 expression. The role of other transporters is discussed in a dedicated section that follows.

Alpha1-Acid Glycoprotein

The binding of drugs to plasma proteins can influence the pharmacokinetics of that drug. A large number of drugs, including PIs, bind extensively to alpha1-acid glycoprotein (AAG). Binding is about 95% for the PIs, saquinavir, and ritonavir and 60% for indinavir (36). It has

Table 3 Functional Consequences of MDR1 Polymorphism at Exons 26 and 21

Polymorphism

Study

Ethnicity

Tissue or cell lines

Exon 26 C3435T

Hoffmeyer (31) Sakaeda (32) Nakamura (187) Kim (188)

Drescher (189) von Ahsen (190) Caucasians Min (191) Fellay (20)

Caucasians

Japanese

Japanese

European American and African American Caucasians

Hitzl (86)

Caucasians Caucasians

Duodenum Duodenum

CD56+ cells

PBMC CD56+ cells

Japanese Japanese

Placenta Upper jejunum

MDR1 expression or activity in vitro

Drug tested

Effect

Digoxin

Digoxin

Digoxin

Fexofenadine

Fexofenadine Ciclosporine Ciclosporine Nelfinavir

Rhodamine 123 Tacrolimus

Plasma level higher for

TT subjects Plasma level lower for

TT subjects Plasma level lower for

TT subjects Plasma level lower for

TT subjects No difference No difference No difference Plasma level lower for

TT subjects Rhodamine 123

accumulation higher in CD56+ cells from TT subjects

No difference

Roberts (193) Caucasians

Exon 21 G2677T/A

(Ala893Ser/Thr)

Exons 21 and 26 Haplotype 2677/3435

Tanabe (192)

Kimchi-Sarfety (194)

Johne (195) Kurata (196)

European American and

Africanm American Japanese

Caucasians

Japanese

NIH-3T3 cells Placenta HeLa cells aNot statistically significant.

Abbreviations'. ND, not done; PBMC, peripheral blood mononuclear cells. Source: From Ref. 30.

Nortriptyline

TT associated with nortriptline-associated hypotension, with no statistical difference in blood levels

Fexofenadine

Digoxin Digoxin

Plasma level lower for TT subjects

Multiple drugs tested in vitro. No difference in expression or activity

Highest plasma levels for Haplotype 12 {2677G/3435T) Highest plasma levels for Haplotype 2677T/3435T

been shown in AAG overexpressing transgenic mice that elevated AAG levels reduce the volume of distribution and systemic clearance of saquinavir (37). Unbound drug represents not only the drug available for exerting the pharmacological effect, but it also influences the tissue and cellular penetration of drugs into cells, because only unbound drug in the plasma can equilibrate with intracellular compartments. This is particularly relevant for PIs, the activity of which is likely to take place intracellularly during assembly and budding of new virions. Several in vitro studies have shown that physiological concentrations of AAG substantially affect the antiviral potency of several PIs. An elevated AAG concentration can reduce uptake and decrease intracellular antiviral activity of various PIs, such as saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir (36,38-40).

Genetic polymorphism of ORM (encoding AAG) and various alleles corresponding to the two loci have been reported (41). The first locus has two main variants (ORM1 S and ORM1 F1), whereas the second locus (ORM2) is mainly monomorphic (ORM2 M, originally called ORM2 A). These variants determine three main phenotypes for AAG in the human population, ORM1 F1S/ORM2 M, ORM1 F1/ORM2 M, and ORM1 S/ORM2 M. The two genes differ by 32 nucleotide substitutions in the coding sequence, resulting in 21 amino acid substitutions (42). Three common ORM1 alleles result from A to G transitions at the codons for amino acid positions 20 and 156 in exons 1 and 5, respectively (43).

Control of AAG expression is both at the transcriptional and posttranscriptional level (44-47). One study showed that the proportion of ORM2 varies threefold, representing 17% to 48% of the total AAG variants, whereas ORM1 S and ORM1 F1 represent 0% to 65% and 0% to 89%, respectively (48). Important differences in polymorphisms of the AAG gene have been found in different ethnic populations. In African American populations, up to 14% of the subjects did not express the ORM2 A allele (49), whereas this allele is virtually present in all Caucasian subjects (41,48,49). On the other hand, in the Japanese population, ORM duplication occurs at a frequency as high as 20% (50). No study to date has assessed the relevance of these polymorphisms to the clinical management of HIV disease.

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