Volume Issue June/July Topics in HIV Medicine...Topics in HIV Medicine ® A publication of the International AIDS Society–USA Table of Contents Volume 13 Issue 2 June/July 2005Editorial

Volume 13 Issue 2 June/July 2005

A publication of the International AIDS Society–USAA publication of the International AIDS Society–USA

Topics inHIV Medicine®

Perspectives

Drug-Drug Interactions and the Pharmacotherapy of HIV Infection 64Angela D. M. Kashuba, PharmDAtazanavir/Ritonavir and Saquinavir/Ritonavir • Efavirenz and Buprenorphine •Antiretrovirals and Depomedroxyprogesterone • PI Cytochrome P450 Inhibition andInduction: Lopinavir/Ritonavir and Phenytoin • Double-Boosted PIs • Tenofovir andDidanosine

Metabolic Complications of Antiretroviral Therapy 70Donna E. Sweet, MDClinical Implications of Metabolic Abnormalities • Lipodystrophy • Dyslipidemia andCoronary Heart Disease • Glucose Metabolism • Bone Disorders • MitochondrialDisorders

Selected Rare, Noninfectious Syndromes Associated 75

With HIV Infection Molly E. Eaton, MDNucleotide Reverse Transcriptase-Associated Fanconi Syndrome • PulmonaryHypertension • Thrombotic Thrombocytopenic Purpura • Diffuse InfiltrativeLymphocytosis Syndrome • Castleman’s Disease

Review

Sex Differences in the Pharmacologic Effects of 79Antiretroviral Drugs: Potential Roles of Drug Transporters and Phase 1 and 2 Metabolizing EnzymesIghovwerha Ofotokun, MD, MScAntiretroviral Drug Transporters • Antiretroviral Metabolizing Enzymes

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International AIDS Society–USA Topics in HIV Medicine

About This Issue

Topics in HIV Medicine®

Educational grants supported the 2005 HIVPathogenesis, Antiretrovirals, and Other SelectedIssues in HIV Disease Management CME courseprogram. We gratefully acknowledge:

Major Grant Support

Bristol-Myers Squibb Co.Tibotec Therapeutics/Ortho Biotech

Substantial Grant Support

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Generous Grant Support

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GlaxoSmithKline

Funding for selected courses in the 2005 program wereprovided by Merck and Co. and by Pfizer GlobalPharmaceuticals

The International AIDS Society–USA

®

Topics in HIV Medicine (formerly Improving theManagement of HIV Disease) is published by theInternational AIDS Society–USA. This journal isintended to be a resource for physicians andother health care practitioners who are activelyinvolved in HIV and AIDS care.

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ISSN 1542-8826Printed in USA on acid-free paper July 2005© 2005 International AIDS Society–USA

This issue features 3 Perspectives articles based on presentations from

the International AIDS Society–USA continuing medical education

courses held in New York, Atlanta, and Los Angeles in March and April

of this year. Angela D. M. Kashuba, PharmD, described recent findings

in drug-drug interactions and the pharmacotherapy of HIV infection.

Donna E. Sweet, MD, outlined the metabolic complications associated

with antiretroviral therapy and discussed issues such as risk factors and

drug selection. Molly E. Eaton, MD, described the characteristics, diag-

nosis, treatment, and prognosis of several uncommon noninfectious

syndromes associated with HIV infection.

This issue also features a Review article by Ighovwerha Ofotokun, MD,

MSc, examining sex-related differences in the pharmacologic effects of

antiretroviral drugs and the role that drug transporter genes, proteins,

and enzymes might play in these observed differences.

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A publication of the International AIDS Society–USA

Table of Contents Volume 13 Issue 2 June/July 2005

Editorial BoardDouglas D. Richman, MDEditor in ChiefProfessor of Pathology and MedicineUniversity of California San Diego andVeterans Affairs San Diego Healthcare System

Constance A. Benson, MDSpecial Contributions EditorProfessor of MedicineUniversity of Colorado Health Sciences Center

Charles C. J. Carpenter, MDProfessor of MedicineBrown University School of Medicine

Judith S. Currier, MDProfessor of MedicineUniversity of California Los Angeles

Steven G. Deeks, MDAssociate Clinical Professor of MedicineUniversity of California San Francisco

Roy M. Gulick, MD, MPHAssociate Professor of MedicineWeill Medical College of Cornell University

Martin S. Hirsch, MDProfessor of MedicineHarvard Medical School

Daniel R. Kuritzkes, MDAssociate Professor of MedicineHarvard Medical School

International AIDS Society–USABoard of DirectorsConstance A. Benson, MDProfessor of MedicineUniversity of Colorado Health Sciences Center

Peter C. Cassat, JDMemberDow, Lohnes & Albertson, PLLC

Judith S. Currier, MDProfessor of MedicineUniversity of California Los Angeles

Carlos del Rio, MDAssociate ProfessorEmory University

Joel E. Gallant, MD, MPHAssociate ProfessorJohns Hopkins University

Roy M. Gulick, MD, MPHAssociate ProfessorWeill Medical College of Cornell University

Donna M. JacobsenExecutive DirectorInternational AIDS Society–USA

Douglas D. Richman, MDProfessor of Pathology and MedicineUniversity of California San Diego andVeterans Affairs San Diego Healthcare System

Michael S. Saag, MDProfessor of MedicineThe University of Alabama at Birmingham

Robert T. Schooley, MDProfessor of MedicineUniversity of Colorado Health Sciences Center

Paul A. Volberding, MDChief of the Medical Service San Francisco Veterans Affairs Medical Center Professor of MedicineUniversity of California San Francisco

Staff and ContributorsMichelle Tayag - Production and Web ManagerBrigitte Niquette, Craig High - Layout/GraphicsAmberly Polidor, Katherine L. Kaiser - Editorial AssistantsP. S. Print Smart - PrintingDonna M. Jacobsen - Executive Editor

Perspectives

Drug-Drug Interactions and the Pharmacotherapy of HIV Infection 64Angela D. M. Kashuba, PharmD

Metabolic Complications of Antiretroviral Therapy 70Donna E. Sweet, MD

Selected Rare, Noninfectious Syndromes Associated 75 With HIV Infection Molly E. Eaton, MD

ReviewSex Differences in the Pharmacologic Effects of Antiretroviral Drugs: Potential Roles of Drug Transporters and Phase 1 and 2 Metabolizing EnzymesIghovwerha Ofotokun, MD, MSc

79

AnnouncementsGuidelines for Authors and Contributors 84

Subscription Request 85

Educational Programs 87

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Identical doses of a given drug do notnecessarily produce the same plasmaconcentrations in patients because ofgenetic and environmental differences inabsorption, distribution, metabolism,and excretion. Differences in drug phar-macokinetics may result in differences inpharmacodynamics, augmenting ordiminishing the therapeutic or adverseeffects of a drug. Drug-drug interactionsare one of the factors that can exacerbatepharmacokinetic variability, along withdrug-food interactions, drug-diseaseinteractions (eg, due to alterations in gas-trointestinal, renal, and hepatic func-tion), and sex differences in drug phar-macokinetics, including those associatedwith pregnancy. Understanding druginteractions is crucial to the manage-ment of patients with HIV disease, giventhe multiple antiretroviral agents thatmust be taken and the use of other med-ications for HIV-related and non-HIV-related conditions. Recent findings ondrug-drug interactions in HIV therapy aresummarized herein.

Atazanavir/Ritonavir andSaquinavir/Ritonavir

Omeprazole

A recent study of 48 HIV-uninfected sub-jects indicated that coadministration ofomeprazole 40 mg with atazanavir 300

mg/ritonavir 100 mg markedly reducedatazanavir trough plasma concentrations(Ctrough) (Figure 1; Agarwala et al, 12thCROI, 2005). The effect of omeprazolewas not countered by increasing theatazanavir dose to 400 mg or ingestionof 8 oz of cola to produce an acidic gas-tric/duodenal environment. Omeprazoleconcentrations were not significantlyaltered. It is currently recommended thatthe 2 drugs not be coadministered. One

alternative acid-suppressing agent thatcould be used with atazanavir is famoti-dine. Recently presented data (Agarwalaet al, 6th Int Workshop on ClinPharmacol of HIV Ther, 2005) suggestthat the atazanavir-famotidine interac-tion can be overcome by increasingdoses or temporal dose separation. Toachieve atazanavir systemic concentra-tions similar to those seen with a dose of400 mg once daily, famotidine adminis-tration should be separated by at least10 hours, or atazanavir should be givenwith ritonavir at a dose of 300 mg/100mg once daily. To achieve exposuresequivalent to those seen with anatazanavir/ritonavir regimen of 300mg/100 mg once daily, the atazanavirdose could be increased to 400 mg.

Rifampin

In a study of 71 HIV-uninfected subjects,coadministration of rifampin and

Drug-Drug Interactions and the Pharmacotherapy of HIV InfectionAngela D. M. Kashuba, PharmD

Knowledge of drug-drug interactions is crucial to HIV therapeutics. Recent reports inthis area include reduced atazanavir exposure with coadministration of omeprazoleor rifampin; increased hepatic toxicity with coadministration of saquinavir andrifampin; reduced buprenorphine exposure with concurrent efavirenz administration;absence of clinically significant interactions of depomedroxyprogesterone with nevi-rapine, efavirenz, or nelfinavir; increased atazanavir and saquinavir exposure withthe double-boosted regimen of atazanavir/saquinavir/ritonavir; reduced amprenavir,lopinavir, and saquinavir exposure with the addition of tipranavir/ritonavir therapy;and reduced lopinavir and amprenavir exposure with the addition of fosamprenaviror fosamprenavir/ritonavir to lopinavir/ritonavir. This article summarizes a presenta-tion on drug-drug interactions in HIV therapeutics by Angela D. M. Kashuba, PharmD,at the International AIDS Society–USA course in Los Angeles in April 2005.

Dr Kashuba is an Associate Professor ofPharmacy at the University of NorthCarolina at Chapel Hill.

Atazanavir 300 mg/ritonavir 100 mg

10,000

1,000

100

Ata

zan

avir

Tro

ug

h C

on

cen

trat

ion

(n

g/m

L)

Time (h)

0 2 4 6 8 10 12 14 16 18 20 22 24

Atazanavir 400 mg/ritonavir 100 mg +omeprazole 40 mg

Atazanavir 300 mg/ritonavir 100 mg + omeprazole 40 mg + cola

Atazanavir 300 mg/ritonavir 100 mg + omeprazole 40 mg

Figure 1. Effect of omeprazole on atazanavir trough concentrations in HIV-uninfected sub-jects. Adapted with permission from Agarwala et al, 12th CROI, 2005.

Perspective

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Drug-Drug Interactions Volume 13 Issue 2 June/July 2005

atazanavir 300 mg/ritonavir 100 mgreduced atazanavir exposure, with thereduction again not being countered byan increase in the atazanavir and riton-avir doses to 400 mg and 200 mg,respectively (Figure 2; Burger et al, 12thCROI, 2005). Coadministration ofatazanavir/ritonavir and rifampin shouldbe avoided.

With regard to rifampin and otherboosted protease inhibitors (PIs), arecent Dear Doctor letter describedincreased hepatotoxicity with coadmin-istration of rifampin 600 mg once dailyand saquinavir 1000 mg/ritonavir 100mg twice daily. Elevated liver enzymes(up to 5-fold changes) were detected in40% of the HIV-seronegative subjectsevaluated. The mechanism of the livertoxicity is currently being investigated. Itis recommended that saquinavir/riton-avir and rifampin not be used together.

Efavirenz and Buprenorphine

Buprenorphine is a partial opioid agonistrecently approved for treatment of opi-oid tolerance. In a study of HIV-uninfect-ed patients receiving buprenorphine,treatment with efavirenz for 15 daysresulted in an approximate 50%decrease in buprenorphine exposure(McCance-Katz et al, 12th CROI, 2005).As a percent of pre-efavirenz values,

post-efavirenz values for buprenorphinewere 51% for area under the concentra-tion-time curve (AUC) over 24 hours,55% for maximum concentration (Cmax),49% for minimum concentration (Cmin),and 72% for half-life. Efavirenz concen-trations were within the therapeuticrange. There was no change on the opi-ate withdrawal scale after 15 days; how-ever, the long half-life of buprenorphinemay have precluded seeing pharmacody-namic changes over this short timeframe. This pharmacokinetic interactionis similar to that seen in studies ofefavirenz and methadone. In these stud-ies, symptoms of withdrawal wereobserved only after 3 to 4 weeks. Basedon the currently available data, patientsreceiving efavirenz and buprenorphineshould be closely monitored for symp-toms of withdrawal.

Antiretrovirals andDepomedroxyprogesterone

Evaluation of changes in antiretroviraldrug exposure in women receivingdepomedroxyprogesterone showed littleeffect over 4 weeks. AUC0-12h values over24 hours before and after depomedroxy-progesterone administration were 10.98and 11.14 ng•h/mL for nevirapine(P=0.048), 3.56 and 3.50 ng•h/mL forefavirenz (P=not significant [NS]), 10.49

and 10.29 ng•h/mL for nelfinavir(P=NS), and 8.78 and 8.84 ng•h/mL forthe active M-8 nelfinavir metabolite(P=NS; Cohn et al, 12th CROI, 2005).The small change in nevirapine exposure,although statistically significant, is likelynot clinically significant. There was noevidence of ovulation over the short dura-tion of the study, and none of the womenbecame pregnant. However, the studywas not powered to test the effects ofantiretroviral agents on depomedrox-yprogesterone efficacy. The potential forinteractions of depomedroxyproges-terone with other PIs and with tenofovirneeds to be evaluated.

PI Cytochrome P450 Inhibition and Induction:Lopinavir/Ritonavir andPhenytoin

All PIs are metabolized by (ie, are sub-strates for) the cytochrome P450(CYP450) enzymes; some PIs and somenonnucleoside reverse transcriptaseinhibitors (NNRTIs) inhibit particularCYP450 enzymes, some induce CYP450enzymes, and some both inhibit andinduce these enzymes. Pharmacokineticinteractions may be difficult to predictbased on the relative magnitudes of inhi-bition and induction reported from invitro studies. Further, in vitro studies maybe particularly inaccurate in characteriz-ing enzyme induction, since they maymeasure responses of enzymes removedfrom intact cell systems. Lopinavir andritonavir are metabolized by the CYP3A4enzyme, and the anticonvulsant pheny-toin is an inducer of CYP3A4; coadminis-tration would thus be predicted to resultin decreased lopinavir and ritonavir lev-els. Phenytoin is metabolized via theCYP2C9 and CYP2C19 enzymes, andlopinavir/ritonavir is reported to be aninhibitor of both enzymes; coadministra-tion would thus be expected to result inincreased phenytoin levels. In a study inwhich lopinavir/ ritonavir and phenytoinwere coadministered, lopinavir AUC andCtrough were reduced by 33% and 46%,respectively; ritonavir AUC and Ctrough werereduced by 28% and 47%, respectively;and phenytoin AUC and Ctrough werereduced by 31% and 34%, respectively.The reduction in phenytoin levels was anunexpected finding (Lim et al, J AcquirImmune Defic Syndr, 2004). Subsequent

Atazanavir 300 mg/ritonavir 100 mg +rifampin

100,000

10,000

1,000

100

10

Ata

zan

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Tro

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on

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(n

g/m

L)

Time (h)

0 2 4 6 8 10 12 14 16 18 20 22 24

Atazanavir 300 mg/ritonavir 100 mg

Atazanavir 400 mg



Figure 2. Effect of rifampin on atazanavir trough concentrations in HIV-uninfected subjects.Adapted with permission from Burger et al, 12th CROI, 2005.

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investigation of the effects of lopinavir/ritonavir in non-HIV-infected volunteersshowed that in vivo lopinavir is an induc-er of CYP2C9 (approximate 25%increase) and CYP2C19 (approximate75% increase; Yeh et al, 5th IntWorkshop on Clin Pharmacol of HIVTher, 2004).

Double-Boosted PIs

Atazanavir/Ritonavir Plus Saquinavir

There is considerable interest in using 2PIs with pharmacokinetic boosting fromritonavir—for example, to increase PIlevels in patients with prior extensivetreatment so that each PI might retainactivity against virus resistant to theother PI. Such a strategy entails investi-gation of the pharmacokinetic interac-tions of the drugs considered for use. Inone study, 40 patients receivedatazanavir 300 mg/ritonavir 100 mgdaily plus saquinavir 1000 mg twicedaily, 50 received atazanavir 300mg/ritonavir 100 mg daily plus an nRTI

twice daily, and 100 received saquinavir1000 mg/ritonavir 100 mg twice dailyplus an nRTI twice daily (Von Hentig etal, XV Int AIDS Conf, 2004). It was foundthat the addition of saquinavir signifi-cantly increased the Cmin of atazanavir,compared with that of atazanavir/riton-avir, and that the AUCs of both atazanavirand saquinavir significantly increasedwith the double-boosted regimen, com-pared with the single-boosted regimens.Sex and coadministration of tenofovirdid not appear to have any effect onatazanavir AUC at steady state. The dou-ble-boosted regimen of atazanavir/riton-avir plus saquinavir at full therapeuticdoses thus does not appear to have detri-mental pharmacokinetic interactions.

Tipranavir/Ritonavir

In contrast, it was found in one studythat adding PIs to a tipranavir 500mg/ritonavir 200 mg regimen results in adetrimental interaction among the PIs.As shown in Figure 3, the AUC, Cmax, andCmin of ritonavir-boosted amprenavir,

lopinavir and saquinavir decreasedmarkedly with the addition of tipranavir(Walmsley et al, XV Int AIDS Conf, 2004).This effect was not expected on the basisof the effects of tipranavir/ritonavir onhepatic CYP3A enzyme activity. Themechanism of the interaction is unclear,although it may relate to the effects oftipranavir on drug transporter activity, ora physical incompatibility of drugs in thegut.

Lopinavir/Ritonavir PlusFosamprenavir

The A5143 study of lopinavir/ritonavirand fosamprenavir was the first evalua-tion intended to prospectively assess theefficacy of a double-boosted PI regimencompared with 2 single-boosted PI regi-mens. However, in a pharmacokineticsubstudy, a significant interaction amongthe drugs was found, resulting in discon-tinuation of the study (Kashuba et al,AIDS, 2005; Wire et al, 11th CROI, 2004).As shown in Table 1, marked reductionsin lopinavir and amprenavir AUC values

Table 1. Effect of Fosamprenavir or Fosamprenavir/Ritonavir and Lopinavir/Ritonavir Coadministration on Lopinavir andAmprenavir Exposure

Regimen/parameter

Control 1

Lopinavir/ritonavir+fosamprenavir

Geometric mean ratio1



Lopinavir/ ritonavirdose (mg)

400/100 bid

400/100 bid

400/100 bid

533/133 bid

AUC0-12h

93 (µg•h/mL)

48 (µg•h/mL)

0.52

1.37

0.95

C12h

5.8 (µg/mL)

2.3 (µg/mL)

0.39

1.52

1.01

Fosamprenavirorfosamprenavir/ritonavirdose (mg)

700/100 bid

700 bid

700/100 bid

1400 bid

AUC0-12h

41.8 (µg•h/mL)

15.2 (µg•h/mL)

0.36

0.37

0.75

C12h

2.3 (µg/mL)

0.7 (µg/mL)

0.31

0.35

0.58

1Kashuba et al, AIDS, 2005 2Wire et al, 11th CROI, 2004

AUC0-12h indicates area under the concentration-time curve from 0 to 12 hours; C12h, 12-hour concentration; bid, twice daily.

Lopinavir Amprenavir

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were observed with concomitant admin-istration of lopinavir 400 mg/ritonavir100 mg twice daily and fosamprenavir700 mg twice daily. Boosting fosampre-navir 700 mg with ritonavir 100 mgtwice daily resulted in increasedlopinavir concentrations but notincreased amprenavir concentrations.Increasing the lopinavir/ritonavir dose to533 mg/133 mg twice daily and the fos-amprenavir dose to 1400 mg twice dailybrought lopinavir concentrations to con-trol values, but amprenavir concentra-tions remained reduced. Additionally,this regimen was associated with signifi-cant toxicity. In another strategy to over-come what might be physical incompati-bility of the 2 agents in the gut, lopinavir800 mg/ritonavir 200 mg and fosampre-navir 1400 mg/ritonavir 200 mg weregiven once daily, 12 hours apart.Lopinavir exposure was similar to controlvalues, but amprenavir exposure was stilldramatically reduced (Corbett et al, 11thCROI, 2004). Data from the 56 patientsenrolled in A5143 before the study wasstopped indicated no significant differ-ences between lopinavir/ritonavir plusfosamprenavir and lopinavir/ritonavir orfosamprenavir/ritonavir in virologicresponse rate (75% and 61%, respec-tively), CD4+ cell count response(increases of 81/µL and 41/µL, respec-

tively), or reduction of plasma HIV RNAlevel to 50 copies/mL (54% and 46%,respectively; Collier et al, 12th CROI,2005). Although the authors have con-cluded that the reduced drug exposuredid not adversely affect response, sincethe hypothesis of the trial was that dou-ble boosting would improve virologicresponse, an adverse virologic effect ofthe interaction cannot be excluded.

Tenofovir and Didanosine

Among nRTIs, there are interactionsbetween tenofovir and didanosinedespite the fact that they are not metab-olized to active form via the same intra-cellular pathways. Tenofovir also haspharmacokinetic interactions withlopinavir/ritonavir, atazanavir, atazanavir/ritonavir, and tipranavir/ritonavir, indicat-ing that nRTIs may sometimes affectmetabolism of agents that are hepatical-ly metabolized. Some of these may beoccurring through transporter-mediatedinteractions. In the case of tenofovir anddidanosine, coadministration has beenfound to increase didanosine AUC by44% to 60%. The mechanism of interac-tion appears to involve the catabolicpathway for didanosine, in which thedrug is metabolized to other compounds

by purine nucleoside phosphorylase(PNP) and then eliminated in the urine.PNP is ubiquitous in the body, and isknown to be present in erythrocytes,which are believed to be one of the mainroutes for didanosine elimination.Didanosine is the only antiretroviralagent known to be cleared by PNP.Tenofovir monophosphate and diphos-phate have significant affinity for PNPand inhibit PNP degradation of didano-sine (Ray et al, Antimicrob AgentsChemother, 2004).

A number of adverse pharmacody-namic effects have been observed withthe combination of tenofovir anddidanosine, and it is possible that someof these are related to the same pharma-cokinetic mechanism. A retrospectiveanalysis comparing CD4+ cell countchange over 48 weeks in patients onstandard-dose tenofovir plus didanosinewith those on either tenofovir or didano-sine for reasons other than virologic fail-ure showed that only patients receivingthe combination exhibited a significantdecline in CD4+ cell count (50% >100cells/µL, 30% >200/µL), despite viralload remaining below limits of assaydetection (Negeredo et al, AIDS, 2004). Asubset of patients who had the didano-sine dose reduced to 250 mg exhibitedCD4+ cell count increases that did not,however, reach baseline levels. In anoth-er cohort of 295 patients receiving teno-fovir, the probability of developing K65R(particularly in the setting of a triple-nucleoside regimen) substantially in-creased with concomitant didanosine orabacavir therapy. The frequency of themutation was negligible in boosted PIregimens and low in tenofovir regimensthat did not include abacavir or didano-sine, and the addition of zidovudine totreatment substantially reduced risk ofthe mutation (Staszewski et al, 44thICAAC, 2004). An increased risk ofhyperglycemia was observed in patientsreceiving tenofovir plus didanosine com-pared with those receiving only tenofoviror didanosine, with 60% of thesepatients receiving a reduced dose ofdidanosine (Garcia-Benayas et al, 12thCROI, 2005). However, a poor immuno-logic response was not seen in a retro-spective analysis of 219 patients treatedwith tenofovir plus didanosine, 89% ofwhom were receiving the 250 mg doseof didanosine (Karrer et al, 12th CROI,2005).

Amprenavir SaquinavirLopinavir1.2

1

0.8

0.6

0.4

0.2

0

Geo

met

ric

Mea

n R

atio

(+/-

90%

Co

nfi

den

ce In

terv

al)

◆

AUC Cmax Cmin

◆◆ ◆

◆

◆◆

◆

◆

◆ ◆ ◆

Figure 3. With-tipranavir to without-tipranavir ratio of amprenavir, lopinavir, and saquinavirarea under the concentration-time curve (AUC), maximum concentration (Cmax), and mini-mum concentration (Cmin) for amprenavir/ritonavir, lopinavir/ ritonavir, and saquinavir/riton-avir. Adapted with permission from Walmsley et al, XV Int AIDS Conf, 2004.

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It has been hypothesized that theCD4+ cell decline with the tenofovir/didanosine combination and the failureof triple-nRTI regimens including eithertenofovir/didanosine or tenofovir/aba-cavir may be related to the effects onPNP (Kakuda et al, AIDS, 2004). PNP isinvolved in both the adenine and gua-nine metabolic pathways, in which it cat-alyzes the degradation of the purines tohypoxanthine and guanine. It is knownthat a hereditary deficiency in PNP isassociated with increased deoxyguano-sine triphosphate (dGTP) and deoxyade-nosine triphosphate (dATP) levels, severelymphopenia, and reduced T-cell numberand function. Given the effect of teno-fovir in inhibiting PNP and increasingdidanosine concentrations, the questionshave been posed whether (1) the lym-phocyte toxicity observed with the full-dose combination is caused by PNP inhi-bition resulting in excess nucleotides;and (2) the failure of triple–nRTI therapywith tenofovir/abacavir/lamivudine andtenofovir/didanosine/lamivudine is relat-ed to imbalance in the deoxynucleotidetriphosphate (dNTP) to dideoxynu-cleotide triphosphate (ddNTP) pools as aresult of PNP inhibition. These potentialeffects of PNP inhibition are currentlybeing investigated.

Conclusion

The potential for drug interactions in thetreatment of HIV infection and its com-plications is unprecedented. The virtuallylimitless number of drug combinationsthat may be taken by patients undergo-

ing treatment of HIV infection makespharmacokinetic and pharmacodynamicdrug-drug interactions almost inevitable.This presentation reviewed some of themore important recent pharmacologyfindings. Up-to-date information can alsobe found on the Web sites listed in Table2, which also contain links to a largenumber of other resources.

Presented in April 2005. First draft preparedfrom transcripts by Matthew Stenger.Reviewed and updated by Dr Kashuba in June2005. Dr Kashuba is grateful to Dr CourtneyFletcher for initially developing the lecturematerials.

Financial Disclosure: Dr Kashuba hasreceived grant and research support fromAbbott, Gilead, and GlaxoSmithKline. She hasalso served as a consultant to BoehringerIngelheim and Roche.

Suggested Reading

Agarwala S, Gray K, Wang Y. Pharmaco-kinetic effect of omeprazole on atazanavirco-administered with ritonavir in healthysubjects. [Abstract 658.] 12th Conferenceon Retroviruses and OpportunisticInfections. February 22-25, 2005; Boston,MA.

Agarwala S, Eley T, Villegas C, et al.Pharmacokinetic effect of famotidine onatazanavir with and without ritonavir inhealthy subjects. [Abstract 11.] 6thInternational Workshop on ClinicalPharmacology of HIV Therapy. April 28-30,2005; Quebec City, Quebec.

Burger D, Agarwala S, Child M, Wang Y,Grasela D. Effect of rifampin on steady-state pharmacokinetics of atazanavir andritonavir in healthy subjects. [Abstract657.] 12th Conference on Retroviruses andOpportunistic Infections. February 22-25,2005; Boston, MA.

Cohn SE, Watts D, Lertora J, Park JG, Yu S,the A5093 Team. An open-label, non-ran-domized study of the effect of depo-medroxyprogesterone acetate on the phar-macokinetics (PK) of selected proteaseinhibitors and non-nucleoside reverse tran-scriptase inhibitors therapies among HIV-infected women. [Abstract 82.] 12thConference on Retroviruses and

Opportunistic Infections. February 22-25,2005; Boston, MA.

Collier A, Tierney C, Downey G, et al.Randomized study of twice-daily lopinavir/ritonavir or fosamprenavir + ritonavir vslopinavir/ritonavir + fosamprenavir (withtenofovir DF and nucleosides) as rescuetherapy. [Abstract 577.] 12th Conferenceon Retroviruses and OpportunisticInfections. February 22-25, 2005; Boston,MA.

Corbett AH, Davidson L, Park JJ, et al. Doseseparation strategies to overcome the phar-macokinetic interaction of a triple proteaseinhibitor regimen containing fosampre-navir lopinavir, and ritonavir. [Abstract611.] 11th Conference on Retroviruses andOpportunistic Infections. February 8-11,2005; San Francisco, CA.

Garcia-Benayas T, Barrios A, Sanchez-Conde M, et al. Higher risk of hyper-glycemia in patients under didanosine- andtenofovir-containing regimens. [Abstract829.] 12th Conference on Retroviruses andOpportunistic Infections. February 22-25,2005; Boston, MA.

Kakuda TN, Anderson PL, Becker SL. CD4cell decline with didanosine and tenofovirand failure of triple nucleoside/nucleotideregimens may be related. AIDS. 2004;18:2442-2444.

Karrer U, Ledergerber B, Weber R, et al. Noevidence for poor immunologic response inpatients treated with a combination oftenofovir and didanosine at 250 mg daily.[Abstract 588.] 12th Conference onRetroviruses and Opportunistic Infections.February 22-25, 2005; Boston, MA.

Kashuba AD, Tierney C, Downey GF, et al.Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavirand lopinavir exposure: ACTG protocolA5143 results. AIDS. 2005;19:145-152.

Lim ML, Min SS, Eron JJ, et al.Coadministration of lopinavir/ritonavir andphenytoin results in two-way drug interac-tion through cytochrome P-450 induction. JAcquir Immune Defic Syndr. 2004;36:1034-1040.

McCance-Katz EF, Pade P, Friedland G,Morse G, Moody D, Rainey P. Efavirenzdecreases buprenorphine exposure, but is

Table 2. Pharmacology InformationResources

• http://aidsinfo.nih.gov (formerly www.hivatis.org)

• www.thebody.com(general information and news)

• www.iasusa.org(International AIDS Society–USA)

• www.hivinsite.org(University of California San Francisco)

• www.aidsmeds.com

• www.hivpharmacology.com

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not associated with opiate withdrawal inopioid dependent individuals. [Abstract653.] 12th Conference on Retroviruses andOpportunistic Infections. February 22-25,2005; Boston, MA.

Negeredo E, Molto J, Burger D, et al.Unexpected CD4 cell count decline inpatients receiving didanosine and teno-fovir-based regimens despite undetectableviral load. AIDS. 2004;18: 459-463.

Ray AS, Olson L, Fridland A. Role of purinenucleoside phosphorylase in interactionsbetween 2′, 3′-dideoxyinosine and allopuri-nol, ganciclovir, or tenofovir. AntimicrobAgents Chemother. 2004;48:1089-1095.

Staszewski S, Dauer B, Stuermer M, et al.Predictors of K65R development with teno-fovir DF (TDF)-containing regimens in HIVtherapy-experienced patients. [Abstract H-

177.] 44th Interscience Conference onAntimicrobial Agents and Chemother.October 30-November 2, 2004;Washington, DC.

Von Hentig NH, Mueller A, Haberl A, et al.The ATSAQ-1 cohort study; pharmacokinet-ic interactions of atazanavir (ATV) andsaquinavir (SAQ) in a ritonavir (RTV) boost-ed protease inhibitor regimen. [AbstractWeOrB1235.] XV International AIDSConference. July 11-16, 2004; Bangkok,Thailand.

Walmsley S, Leith J, Katlama C, et al.Pharmacokinetics and safety of tipranavir/ritonavir (TPV/r) alone and in combinationwith saquinavir (SQV), amprenavir (APV),or lopinavir (LPV): Interim analysis ofBI1182.51. [Abstract WeOrB1236.] XVInternational AIDS Conference. July 11-16,2004; Bangkok, Thailand.

Wire MB, Naderer OJ, Masterman AL, Lou Y,Stein DS. The pharmacokinetic interactionbetween GW433908 and lopinavir/ritonavir(APV10011 and APV10012). [Abstract 612.]11th Conference on Retro- viruses andOpportunistic Infections. February 8-11,2005; San Francisco, CA.

Yeh RF, Gaver VE, Park JJ, et al. Lopinavir/ritonavir induces CYP2C9 and 2C19 activity,as measured by warfarin and omeprazolebiomarkers in healthy human volunteers.[Abstract 4.1.] 5th International Workshopon Clinical Pharmacology of HIV Therapy.April 1-3, 2004; Rome, Italy.

Top HIV Med. 2005;13(2):64-69.Copyright 2005, International AIDS Society–USA

A special offer for non-ID HIV clinicians

National HIV/AIDS UpdateOctober 7-9, 2005 San Francisco

HIV clinicians from across the country will gather for this state-of-the-art clinical update to review hot topics, exchange information about the latest advances in HIV care and participate

in an interactive case review session, among many other activities; all at a special discounted meeting rate.

For Program and Registration Information, Please visit www.idsociety.org/HIVUpdatePreregistration Deadline: September 16, 2005

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Many advances have been made inunderstanding the pathogenesis and pro-gression of HIV disease, developing effec-tive antiretroviral agents and regimens,learning how best to use these regimensfor prolonged maximal viral suppression,lowering the pill burden of regimens, andmanaging many acute adverse effects oftreatment. The problems for manypatients on long-term effective antiretro-viral therapy are the long-term metaboliccomplications of treatment. Much workremains to be done in identifying howbest to avoid these complications andhow to effectively treat them when theycannot be avoided.

Clinical Implications of Metabolic Abnormalities

HIV-infected patients receiving long-termantiretroviral therapy exhibit a numberof metabolic complications, includinglipid abnormalities, dysregulation of glu-cose metabolism, body-fat redistribution,mitochondrial abnormalities, and boneabnormalities, as well as the sequelae ofthese disorders. The etiology of theseabnormalities remains largely undefined,and it is unclear whether they representindividual or multiple syndromes. Theprospect of patients ultimately experi-encing these abnormalities influencesthe timing of initiation of antiretroviraltherapy, since the risk of long-term toxic-ity must be considered against the viro-logic and immunologic benefits of earlytreatment. The risk of these abnormali-

ties should also influence the choice ofinitial therapy, and the selection shouldbe individualized as much as possiblebased on risk factors for the abnormali-ties. The metabolic derangements havean impact on adherence to therapy,which threatens efficacy, and their pres-ence may limit options in salvage thera-py. Specific strategies to minimize theoccurrence of these abnormalities, suchas simplification of regimens, need to bedeveloped to preserve the efficacy ofantiretroviral treatment.

Lipodystrophy

Lipodystrophy, including lipoatrophy(wasting) and lipohypertrophy (accumu-lation), has occurred in an estimated40% to 50% of patients on long-termtreatment, and the morphologic changeshave a substantial impact on patientquality of life. The lack of a standardizedcase definition for lipodystrophy compli-cates characterization, diagnosis, andtracking of the disorder. The etiology ofthe abnormalities remains unknown,although it appears to be multifactorialand influenced by specific antiretroviraldrugs, host factors such as age andgenetics, and HIV disease stage. Becausethere are probably multiple causes of fatredistribution, it is unlikely that a singleuniform treatment approach will be suc-cessful. Management strategies for lipo-dystrophy include exercise and diet,switching of antiretroviral drugs, anabol-ic steroids, testosterone, recombinanthuman growth hormone, metformin andglitazone treatment, lipid-lowering thera-py, and plastic surgery. The benefits ofmost of these strategies remain largelyunproven.

With regard to risk associated withparticular nucleoside reverse transcrip-tase inhibitors (nRTIs), a number of stud-ies have shown that the use of an nRTIbackbone of didanosine/stavudine isassociated with greater fat loss than iszidovudine/lamivudine (eg, the AIDSClinical Trials Group [ACTG] 384 study) orabacavir/lamivudine (eg, Strategies forManagement of Antiretroviral Therapy–Terry Beirn Community Programs forClinical Research on AIDS [SMART-CPCRA] study 065C). A recent reportfrom the metabolic substudy in theFIRST study showed reductions in totaland regional fat in patients receivingdidanosine/stavudine but not in thosereceiving abacavir/lamivudine over 32months (Shlay et al, XV Int AIDS Conf,2004). Increases in body cell mass andfat were observed in both treatmentgroups through month 12. However,overall changes from month 0 to 32 forthe didanosine/stavudine and abacavir/lamivudine treatment arms, respectivelywere −0.08 kg/month and +0.08kg/month in total body fat, −0.18cm/month and +0.10 cm/month in hipcircumference, −0.21 cm2/month and+0.05 cm2/month in mid-arm skinfoldfat area, and −0.62 cm2/month and+0.62 cm2/month in waist skinfold fatarea (P<.05).

A number of studies on drug switch-ing were reported at the recentConference on Retroviruses andOpportunistic Infections. In brief, find-ings in these studies indicate that substi-tuting a protease inhibitor (PI) with anonnucleoside reverse transcriptaseinhibitor (NNRTI) appears safe, decreasesinsulin resistance, usually reduces triglyc-eride levels, has inconsistent effects ontotal cholesterol and high-densitylipoprotein (HDL) cholesterol levels, andhas no consistent effects on fat gain orloss. Other findings indicated that aba-cavir substitution for stavudine results inincreased subcutaneous adipose tissue(SAT) but no change in visceral adiposetissue (VAT).

Findings to date on studies of theeffects of rosiglitazone in lipodystrophyindicate that it may not be effective in

Metabolic Complications of Antiretroviral TherapyDonna E. Sweet, MD

HIV–infected patients receiving long-term antiretroviral treatment experience a num-ber of metabolic abnormalities, including lipid abnormalities, dysregulation of glu-cose metabolism, body-fat redistribution, mitochondrial abnormalities, and boneabnormalities, as well as the sequelae of these disorders. These complications can besevere and life threatening, disrupt adherence to antiretroviral therapy, limit optionsin therapy, and profoundly affect quality of life. Risk for such complications should beconsidered in selection of antiretroviral therapy, and patients should be monitoredfor the occurrence of abnormalities and changes in risk factors. This article summa-rizes a presentation by Donna E. Sweet, MD, on the metabolic complications of long-term antiretroviral therapy at the IAS–USA course in New York in March 2005.

Dr Sweet is a Professor of Medicine at theUniversity of Kansas School of Medicine inWichita.

Perspective

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increasing subcutaneous fat in patientswith lipoatrophy alone but may increasefat mass in those with both insulin resis-tance and lipoatrophy. Treatment withthis agent improves insulin sensitivity,hyperinsulinemia, and adiponectin lev-els, but may result in increased total andlow-density lipoprotein (LDL) cholesterollevels. Further studies with newer glita-zones are needed to define subpopula-tions of patients most likely to benefitfrom such treatment.

Dyslipidemia and CoronaryHeart Disease

Traditional cardiovascular risk factorscontribute to cardiovascular disease inHIV-infected patients and these risk fac-tors need to be managed aggressively.HIV-infected patients appear to be atincreased risk of coronary heart disease(CHD), as well as for diabetes and hyper-tension, both major risk factors for CHD.Antiretroviral therapy appears to acceler-ate the progression of insulin resistanceand dyslipidemia. A recent study hasindicated that HIV infection alone, priorto initiation of therapy, is associated withincreased cholesterol levels and anadverse effect on insulin sensitivity (El-Sadr et al, HIV Med, 2005). HIV-mediatedinflammation may also play a role inaccelerated CHD. Treatment of risk fac-tors for CHD is complicated by drug-drugand drug-disease interactions in HIV-infected patients. Further studies areneeded to understand the pathogenesisof dyslipidemia and cardiovascular dis-ease in HIV-infected patients.

Some of the data indicating anincreased risk of cardiovascular diseasein the HIV-infected population include aVeterans Administration study showingcardiovascular disease rates of 11.8 per1000 person-years in HIV-infectedpatients, compared with 8.1 per 1000person-years in HIV-uninfected individu-als matched for age and sex. In the DataCollection of Adverse Events of Anti-HIVDrugs (D:A:D) study, conducted in 11cohorts in Europe, Australia, and theUnited States, 126 cases of myocardialinfarction (MI), 28% of which were fatal,were found in 36,479 person-years ofobservation. The relative risk for MI inHIV-infected patients on long-term thera-py was 1.26 per year of therapy; a recentupdate after an additional year of follow-up indicates a relative risk of 1.17 peryear of antiretroviral therapy (Sabin et al,12th CROI, 2005). Another study hasreported that patients with AIDS have arelative risk of 10.4 for stroke. Anotherhas suggested that carotid artery intimamedia thickness, a surrogate marker forcoronary disease, is greater and increas-es more rapidly in HIV-infected patientsthan in age-matched controls.

Recommendations for treating dys-lipidemia in HIV-infected patients toreduce cardiovascular risk include follow-ing the National Cholesterol EducationPanel (NCEP) recommendations for thegeneral population, including institutionof diet and exercise and smoking cessa-tion. Drug-drug interactions and livertoxicity in association with HIV–hepatitisB or C virus coinfection need to be takeninto careful consideration when selecting

lipid-lowering drug therapy. For drugtherapy, statin treatment may consist ofpravastatin 40 mg or atorvastatin 5 or 10mg; higher doses of atorvastatin may beneeded if patients are taking efavirenz.Low-dose fluvastatin may also be consid-ered, with careful dose titration; fluvas-tatin should not be used if the patient istaking saquinavir/ritonavir or nelfinavir.Simvastatin and lovastatin should beavoided until further pharmacokineticsstudies are performed to identify druginteractions. Fenofibrate 160 mg mayalso be used to treat dyslipidemia. Otheragents under study in the HIV-infectedpopulation include niacin, fish oil, andezetimibe. A recent study indicated thatfish oil taken 3 times daily produced alarge decrease in triglycerides in hyper-triglyceridemic patients, although levelsremained elevated above normal (Wagh,Expert Rev Cardiovasc Ther, 2004). Forpatients in whom hyperlipidemia is pre-sent before beginning antiretroviral ther-apy, regimens containing atazanavir,tenofovir, or efavirenz may be appropri-ate to have less effect on lipid profiles. Asshown in Figure 1, both atazanavir-basedand efavirenz-based therapies resulted instability or an increase in appendicularand truncal fat on dual energy x-rayabsorptiometry scan and increased SATand VAT on computed tomography in theBMS-034 study (Noor et al, XV Int AIDSConf, 2004).

With regard to the effects of anabolicsteroid treatment on lipid profiles and fatdistribution, a recent 12-week study in32 patients indicated that oxandrolonewith exercise caused worsening in lipid

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Figure 1. Changes in body fat (left) on dual energy x-ray absorptiometry (DEXA) and in abdominal fat (right) on computed tomography (CT)over 48 weeks of efavirenz-based (EFV) or atazanavir-based (ATV) treatment in the BMS-034 study. Adapted with permission from Noor et al,XV Int AIDS Conf, 2004.

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measures (increased LDL cholesterol andreduced HDL cholesterol levels) com-pared with exercise alone (Figure 2); how-ever, the study groups were not wellmatched for lipid variables at baseline(Smith et al, XV Int AIDS Conf, 2004).

Glucose Metabolism

Abnormalities of glucose homeostasis,primarily insulin resistance, are commonin patients on antiretroviral therapy, witha greater frequency of abnormalitiesobserved in patients receiving PIs. Themechanisms of these abnormalitiesremain largely undefined. Managementincludes encouraging weight loss foroverweight individuals. Treatment withinsulin-sensitizing agents may be benefi-cial; diabetes treatment guidelines shouldbe followed in HIV-infected individuals.

Recent findings in this area include anassociation of hyperinsulinemia with thedorsocervical fat deposit termed “buffalohump” in HIV-infected patients (Mallon etal, J Acquir Immune Defic Syndr, 2005).This finding indicates that patients withbuffalo hump should be closely followedfor insulin resistance and diabetes. It alsosuggests that caution should be exercisedwhen using human growth hormone fortreating buffalo hump, since growth hor-mone is associated with hyperinsulin-emia.

Another recent study indicates thatabnormal glucose metabolism may fuelcognitive dysfunction in HIV-infectedpatients (Valcour et al, J Acquir ImmuneDefic Syndr, 2005). The study indicatedthat diabetes is an independent risk fac-tor for HIV-associated dementia, with thedata hinting that subtle, prediabeticabnormalities in glucose regulation mayalso pose a risk for cognitive impair-ment. Among 203 adult patients aged 20to 76 years (approximately 50% aged>50 years), older patients with diabeteswere more likely to meet the researchclassification of HIV dementia. Afteradjustment for age, education, ethnicity,CD4+ cell count, duration of HIV infec-tion, and PI-based therapy, diabetes wassignificantly associated with risk for HIV-associated dementia, with an odds ratioof 5.43, and the significant associationremained after adjustment for coexistingvascular risk factors for dementia.

Bone Disorders

Osteopenia, osteoporosis, and avascularnecrosis have been reported in patientswith HIV infection. An association ofthese disorders with PI-containing regi-mens with tenofovir has been reportedin the past, but some recent small stud-ies call this into question. Various riskfactors may contribute to these abnor-

malities, including prior steroid treat-ment for avascular necrosis, cigarettesmoking, and hormone therapy forosteoporosis. Clinicians need to be awareof the potential for bone disorders andshould treat them early; however, routinescreening is not recommended. Furtherstudy is needed to identify the etiology ofdecreased bone mineral density, risk fac-tors, and appropriate prevention andtreatment strategies. One recentlyreported study followed bone changesover 144 weeks in initially antiretroviral-naive patients. Approximately 40% ofpatients had osteopenia at baseline, but,with treatment, there was no progressionto osteoporosis over the course of follow-up. However, approximately 40% ofpatients were lost to follow-up, making itdifficult to interpret the study findings.

Mitochondrial Disorders

Mitochondrial toxicity of nRTIs mayunderlie or contribute to many of themetabolic abnormalities associated withthese agents. Older nRTIs (eg, stavudine,didanosine, zidovudine, zalcitabine) areassociated with a greater risk of toxicitythan newer agents (eg, lamivudine,emtricitabine, abacavir, tenofovir).Mitochondrial toxicity has been implicat-ed in neuromuscular toxicities such aspolyneuropathy (zalcitabine, didanosine,

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stavudine), myopathy (zidovudine, dis-anosine), and cardiomyopathy (zidovu-dine, zalcitabine, didanosine); pancreati-tis (didanosine, stavudine); pancyto-penias (zidovudine); hepatic microvesic-ular and macrovesicular steatosis(zidovudine, didanosine, stavudine, zal-citabine); peripheral fat wasting (stavu-dine); and hyperlactatemia and lacticacidosis. The role of HIV per se in mito-chondrial toxicity is not clear.

There are data that indicate recoveryin mitochondrial DNA following a switchto an nRTI-sparing regimen. In onestudy, mitochondrial DNA in both fatbiopsies and peripheral blood mononu-clear cells (PBMCs) increased in patientsswitched from nRTI therapy to an nRTI-sparing regimen (Boyd et al, XV Int AIDSConf, 2004). The gain in fat mitochon-drial DNA was significant only when theswitch was from stavudine, not zidovu-dine, and the increase in DNA in PBMCswas significant only after switching fromzidovudine, not stavudine (Figure 3;Boyd et al, XV Int AIDS Conf, 2004).

Hyperlactatemia and Lactic Acidosis

As noted, hyperlactatemia and lactic aci-dosis appear to be due to nRTI mito-chondrial toxicity, and greater risk isassociated with older nRTIs, such as zal-citabine, didanosine, stavudine, zidovu-dine, lamivudine, and abacavir. The lac-tic acidosis observed is a “type B” lacticacidosis (dysfunction not due to lack ofoxygen supply to tissue), for which mito-chondrial dysfunction is a commonpathophysiologic mechanism. Diagnosis

is difficult because symptoms are vagueand nonspecific. Symptoms include nau-sea and vomiting, abdominal pain orgastric discomfort, unexplained fatigue,malaise, weight loss, and dyspnea.Symptoms may progress to severe, life-threatening metabolic acidosis. Althoughsevere lactic acidosis is relatively rare, ahigh index of suspicion must be main-tained for the disorder in any patientreceiving nRTIs. Prompt discontinuationof the offending nRTI is associated withbetter prognosis. Onset of symptomscannot be predicted by routine monitor-ing of lactate levels. Risk factors includeolder age, obesity, and female sex.Hepatic steatosis usually is present andmay be a key part of the syndrome. Amilder variant of the syndrome mayexist in the form of hyperlactatemiawithout acidosis. Asymptomatic hyper-lactatemia is, however, very rare.

The clinical significance of low-levelhyperlactatemia is unclear. Of concern isthe role of the liver in the syndrome,with the findings being similar to what isobserved in nonalcoholic steatohepatitis.Questions that remain to be answeredinclude whether the condition posespotential for progression to cirrhosis andwhether it is a confounding risk factorfor liver failure in patients coinfectedwith hepatitis B or C virus.

Peripheral Neuropathy

nRTI-associated peripheral neuropathyis characterized by bilateral, symmetric,painful tingling sensations (dysesthesias)in the feet and toes, loss of tendon

reflexes (areflexia), and distal sensoryloss. The disorder is primarily seen withdidanosine and stavudine. It is variablyreversible after stopping nRTI therapy.Nerve biopsies show damaged mito-chondria. The condition is sometimesdifficult to distinguish from neuropathyassociated with HIV infection per se. Riskfactors during nRTI treatment includelow CD4+ cell count (<100/µL), priorhistory of an AIDS-defining illness orneoplasm, prior history of peripheralneuropathy, and use of other neurotoxicagents, including high alcohol consump-tion. Combination therapy with didano-sine and stavudine increases risk of thedisorder.

Pancreatitis

Treatment with didanosine and stavu-dine is associated with a dose-dependentrisk of pancreatitis, with the incidenceprobably ranging from 4% to 7% at cur-rently recommended doses. Mitochon-drial toxicity of nRTIs has been demon-strated in human pancreatic cell lines.

Myopathy and Cardiomyopathy

Myopathy has been seen most common-ly with zidovudine, although it is less fre-quent at current dosing levels.Mitochondrial DNA depletion and abnor-mal mitochondria have been describedin skeletal and endomyocardial musclefrom affected patients. Zidovudine-asso-ciated myopathy is difficult to distinguishfrom that caused by HIV infection per se.In the case of confirmed zidovudine-

Figure 3. Changes in mitochondrial DNA (mtDNA) level in fat (left) and in peripheral blood mononuclear cells (PBMCs; right) over 48 weeksafter switch to nRTI-sparing regimen. After stratification for prior nRTI, increase in fat mtDNA was significant only with switch from stavudine(not zidovudine) and increase in PBMC mtDNA was significant only with switch from zidovudine (not stavudine). Adapted with permissionfrom Boyd et al, XV Int AIDS Conf, 2004.

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associated myopathy and cardiomyopa-thy, clinical and histologic changes arereported to be reversible.

Summary

Patients should be assessed for risk fac-tors for metabolic complications ofantiretroviral therapy prior to initiation oftherapy and should be monitored forsuch complications every 3 to 6 monthsafter starting treatment, at the time ofswitching therapy, and at least annuallythereafter. Routine measurement of fast-ing glucose or glucose tolerance testingand routine monitoring of fasting lipidsare recommended. Routine monitoringof anthropometric measurements,serum lactate levels, and bone densitycurrently is not recommended.

Success of antiretroviral therapy doesnot depend solely on reducing plasmaHIV-1 RNA levels to below 50 copies/mL.Metabolic complications of long-termtherapy threaten the clinical benefits ofsuch effective treatment. Table 1 pro-vides basic guidelines for reducing therisk of metabolic complications.

Presented in March 2005. First draft pre-pared from transcripts by Matthew Stenger.Reviewed and updated by Dr Sweet in June2005.

Financial Disclosure: Dr Sweet has received

grant and research support from Bristol-Myers Squibb, Gilead, and GlaxoSmithKline.She has also served as a scientific advisor toor is on the speakers’ bureaus of Abbott,Agouron, Bristol-Myers Squibb, Gilead,GlaxoSmithKline, Merck, and ViroLogic.

Suggested Reading

Boyd MA, Bien D, Ruxrungtham A, et al.Reversal of mitochondrial DNA and RNAdepletion in patients switched to indi-navir/ritonavir 800/100mg bid andefavirenz 600mg qd after failing NRTI com-bination therapy: a prospective, 48 weeksubstudy of HIV-NAT 009. [AbstractWePpB2064.] XV International AIDS Conf-erence. July 11-16, 2004; Bangkok,Thailand.

El-Sadr WM, Mullin CM, Carr A, et al.Effects of HIV disease on lipid, glucose andinsulin levels: results from a large antiretro-viral-naive cohort. HIV Med. 2005;6:114-121.

Mallon PW, Wand H, Law M, Miller J,Cooper DA, Carr A; HIV LipodystrophyCase Definition Study; AustralianLipodystrophy Prevalence SurveyInvestigators. Buffalo hump seen in HIV-associated lipodystrophy is associated withhyperinsulinemia but not dyslipidemia. JAcquir Immune Defic Syndr. 2005;38:156-162.

Noor MA, Maa J, Giordano MF, Hodder SL.Pattern of adipose tissue redistributionafter initiation of atazanavir-based therapy:analysis of 48-week metabolic and bodycomposition data in treatment-naïvepatients. [Abstract WePeB5874.] XVInternational AIDS Conference. July 11-16,2004; Bangkok, Thailand.

Sabin C, Morfeld L, Friis-Moller N, et al.Changes over time in the use of antiretrovi-ral therapy and risk factors for cardiovascu-lar disease in the D:A:D study. [Abstract866.] 12th Conference on Retroviruses andOpportunistic Infections. February 22-25,2005; Boston, MA.

Shlay JC, Visnegarwala F, Bartsch G, et al.Body composition and metabolic changesin antiretroviral-naive patients randomizedto didanosine and stavudine (ddI+d4T) vs.abacavir and lamivudine (ABC +3TC).[Abstract ThOrB1360.] XV International

AIDS Conference. July 11-16, 2004;Bangkok, Thailand.

Smith BA, Raper JL, Weaver MT, et al.Double blind placebo controlled study ofexercise and oxandrolone on lean mass, fatdistribution, blood lipids, bone density andtraining markers in HIV infected men andwomen on HAART. [Abstract MoOrB1059.]XV International AIDS Conference. July 11-16, 2004; Bangkok, Thailand.

Valcour VG, Shikuma CM, Shiramizu BT, etal. Diabetes, insulin resistance, and demen-tia among HIV-1-infected patients. J AcquirImmune Defic Syndr. 2005;38:31-36.

Wagh A, Stone NJ. Treatment of metabolicsyndrome. Expert Rev Cardiovasc Ther.2004;2:213-228.


Table 1. Guidelines for Reducing Riskof Metabolic Complications

• Think about the metabolic conse-quences of starting or switching antiretroviral therapy

• Assess the patient’s risk factors and modify them when possible

• Lipodystrophy is easier to prevent than to reverse—avoid didanosine/stavudine

• Treat dyslipidemia, insulin resistance, and hypertension aggressively

• Think about lactate levels in patients with suggestive symptoms

• Be vigilant for bone disease—investigatesymptoms, and treat such diseaseappropriately

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Selected Rare, Noninfectious Syndromes Associated With HIV Volume 13 Issue 2 June/July 2005

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Infrequent and treatable noninfectioussyndromes associated with HIV infectioninclude nucleotide reverse transcriptaseinhibitor (ntRTI)-associated Fanconi syn-drome, pulmonary hypertension, throm-botic thrombocytopenic purpura, diffuseinfiltrative lymphocytosis syndrome, andCastleman’s disease. This review willsummarize the characteristics, diagnosis,treatment, and prognosis of these select-ed disorders.

Nucleotide ReverseTranscriptase-AssociatedFanconi Syndrome

Fanconi syndrome is a generalized dys-function of the proximal tubule with noprimary glomerular involvement. It hasbeen observed several weeks after initia-tion of treatment with the ntRTI teno-fovir. Tenofovir undergoes renal excre-tion by active secretion and glomerularfiltration; animal studies raised someconcerns regarding potential bone andrenal toxicity, but clinical trials did notindicate any substantial risk of renal tox-icity.

Fanconi syndrome is characterizedby variable increase in creatinine levels;proteinuria; normoglycemic glycosuria;phosphaturia and hypophosphatemia;potassium wasting and hypokalemia;HCO3 wasting and non-anion gap acido-sis; and polydipsia, polyuria, and dehy-dration. Patients with tenofovir-associat-

ed Fanconi syndrome often present withfatigue, weight loss, and dry mouth. Theworkup for proximal renal tubular dys-function includes serum chemistries toidentify abnormal phosphate, potassi-um, and bicarbonate values; urinalysis toidentify proteinuria and glycosuria; andmeasurement of urine electrolytes (sodi-um, potassium, chloride) to permit cal-culation of the urine anion gap. Renalbiopsy may be indicated in cases inwhich symptoms and biochemicalabnormalities do not resolve after stop-ping tenofovir treatment.

The mechanism of this toxic effect isnot completely clear. Tenofovir in usualconcentrations does not appear to betoxic to renal cells, and the toxic effectmay require accumulation of elevateddrug levels. Tenofovir is imported intothe renal tubule cell via the organic aniontransporter 1 (OAT-1) and efflux occursvia the MRP2 gene-encoded conjugateexport pump. It is thought that thesetransporters may be relatively inefficientin some individuals, allowing accumula-tion of tenofovir within the proximaltubule. Some protease inhibitors (PIs),such as ritonavir and lopinavir, havebeen found to inhibit the pump, and thismay contribute to tenofovir accumula-tion, although this interaction has notbeen proven. Fanconi syndrome is morelikely to occur in patients with unrecog-nized decreased creatinine clearanceprior to the start of tenofovir treatment.

Patients on tenofovir should undergourinalysis and serum phosphate mea-surement every 6 months. Patients withnormal serum creatinine may still have

abnormal creatinine clearance, and thelatter should be calculated prior to begin-ning treatment. The drug should bestopped in patients with evidence of aci-dosis, glycosuria, proteinuria, orhypophosphatemia. Phosphorus supple-mentation is recommended in cases ofisolated low serum phosphate level,although the benefit of such supplemen-tation remains unclear. The toxicity hasbeen found to be mostly reversible.Currently, there are no recommendationsregarding reintroduction of tenofovir in anew regimen once the syndrome hasresolved.

Pulmonary Hypertension

Pulmonary hypertension is more com-mon in the HIV-infected population thanin the general population, with prevalenceestimates of 5 per 1000 versus 2 per mil-lion (Recusani et al, AIDS, 2003). In thegeneral population, pulmonary hyperten-sion is more common in women. Datafrom cases reported in HIV-infected indi-viduals from 1987 to 1999 indicate that54% of cases were in men; however, menaccounted for the majority of the HIV-infected population during this period aswell. No predisposing factor other thanHIV infection is recognized in 82% ofcases, and there is no correlation of onsetwith stage of HIV infection (Mehta et al,Chest, 2000). Presenting signs and symp-toms include fatigue, syncope, and chestpain; progressive shortness of breath hasbeen reported in 85% of cases, pedaledema in 30%, and nonproductive coughin 19%. There usually are signs of right-sided heart failure, including right-sidedgallop, loud P2 heart sound, tricuspidregurgitation murmur, increased jugularvenous distention, and edema.

Workup for the condition is fairlystraightforward after chest x-ray hasshown dilated pulmonary vessels andright-sided cardiomegaly. Electrocardio-gram may show right ventricular and atri-al hypertrophy and right axis deviation.The echocardiogram may show dilated

Selected Rare, Noninfectious Syndromes Associated WithHIV Infection Molly E. Eaton, MD

Infrequent and sometimes treatable noninfectious syndromes associated with HIV dis-ease include tenofovir-associated Fanconi syndrome, a proximal renal tubular disor-der; pulmonary hypertension that appears to be due to HIV-driven inflammationresulting in endothelial proliferation; thrombotic thrombocytopenic purpura, charac-terized by intravascular coagulopathy; diffuse infiltrative lymphocytosis syndrome,which can affect multiple organs; and Castleman’s disease, a lymphoproliferative dis-order that usually occurs in a multicentric form with poor prognosis in HIV-infectedpatients. This article summarizes a presentation on the characteristics, diagnosis, treat-ment, and prognosis of these disorders by Molly E. Eaton, MD, at the InternationalAIDS Society–USA course in Atlanta in March 2005.

Dr Eaton is an Assistant Professor ofMedicine at Emory University School ofMedicine in Atlanta, GA.

Perspective

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right heart chambers, and can excludevalvular lesions that may cause sec-ondary pulmonary hypertension. It canalso identify the high mean pulmonaryarterial pressure. The elevated pressureshould always be confirmed with right-sided catheterization, which also permitsassessment of response to vasodilators.

The causes of HIV-associated pul-monary hypertension remain unclear.Histopathology is the same for HIV-relat-ed pulmonary hypertension and primarypulmonary hypertension in HIV-uninfect-ed persons, showing overgrowth of theendothelium that leads to obstruction. Amutation in the BMPR2 gene that resultsin reduced inhibition of endothelial pro-liferation in cases of familial primary pul-monary hypertension has not been iden-tified in HIV-associated pulmonaryhypertension. In patients with HIV-asso-ciated pulmonary hypertension, pul-monary status continues to deteriorateeven when viral load is well controlled,suggesting that HIV may be a trigger, butnot the sole culprit, in pathogenesis.Further, no HIV is found in lung tissue inaffected individuals. It is thus believedthat the condition may be caused byincreased inflammatory mediators insusceptible individuals, resulting inincreased production of endothelin-1and increased endothelial proliferation.A recent study suggested a role forKaposi’s sarcoma–associated humanherpesvirus 8 (HHV-8) in pulmonaryhypertension in HIV-uninfected individu-als, although the virus could not be iden-tified in 3 patients with HIV-associatedpulmonary hypertension included ascontrols in the study. The findings fromthis study need to be confirmed.

Therapeutic options in patients withHIV-associated pulmonary hypertensionare the same as in HIV-uninfectedpatients, including vasodilator treatmentwith calcium channel blockers, phospho-diesterase blockers (eg, sildenafil), orprostacyclins (eg, epoprostenol infusion).Symptomatic relief is crucial and mayinvolve home oxygen use, diuretics, anddigoxin. Anticoagulant therapy makessense in this context, although there arefew data on its use. Use of antiretroviraltherapy in affected patients is recom-mended, although there are no data toindicate that it is of benefit in reversingthe underlying endothelial proliferation.

Prognosis is very poor for patientswith this disorder, with a median timespan of 6 months from diagnosis todeath. Suppression of viral replicationdoes not improve prognosis. Better NewYork Heart Association functional classi-fication at the time of diagnosis has beenfound to be the only predictor of betteroutcome (Recusani et al, AIDS, 2003).

Thrombotic ThrombocytopenicPurpura

The incidence of all cases of thromboticthrombocytopenic purpura (TTP) in-creased by 16-fold between 1973 and1991. The incidence of TTP in the HIV-infected population likely has contribut-ed to this overall increase, but the precisemagnitude of this contribution remainsunclear. It is imperative to recognize TTPearly because response to treatment isgenerally excellent if intervention is initi-ated early, and the condition can be fatalif it is not treated promptly (Torok et al,Am J Hematol, 1995).

The 5 main symptoms of full-blownTTP are thrombocytopenia, anemia, cen-tral nervous system abnormalities, renaldysfunction, and fever. The primary dys-function is intravascular clotting, whichconsumes platelets and causes an oftenvery marked thrombocytopenia; hemor-rhage is nevertheless uncommon.Shearing forces within the clots result inintravascular hemolysis, manifested ashigh lactate dehydrogenase levels, lowhaptoglobin, high reticulocyte count, andoften a high indirect bilirubin level.Clotting in intracerebral vessels results inischemia that can present as headache,focal deficits, seizure, and coma. Centralnervous system imaging is almost alwaysnegative. Clotting in vessels in the kidneycan be manifested as hematuria andincreased creatinine. Fever is usually butnot invariably present; infection must beruled out in febrile patients. Figure 1shows the classic finding of schistocytes,fragments of red blood cells that havebeen torn apart as they move through aclot; platelets are notably absent in thesmear.

TTP is associated with large multi-mers of von Willebrand factor, resultingfrom a severe deficiency in ADAMTS13, aprotease that cleaves von Willebrand fac-tor into smaller multimers. The mostcommon cause of sporadic TTP isan inhibitory antibody that bindsADAMTS13. Because of immune dysreg-ulation, HIV-infected patients makeinhibitory antibodies to many bloodcomponents, and it is believed that thehigh incidence of TTP in HIV-infectedindividuals is associated with high levelsof inhibitory antibodies to ADAMTS13(Tsai, J Am Soc Nephrol, 2003).

Treatment is plasmapheresis. Afterobtaining a hematology consultation andcontacting the American Red Cross,plasmapheresis should be performed assoon as possible to reduce risk to thebrain and kidney. Plasmapheresisremoves the ADAMTS13 inhibitor, infus-es large volumes of plasma that diluteinhibitor concentrations, and replenishesADAMTS13. In cases in which plasma-pheresis is not available, plasma infu-sions may be helpful, although the pres-ence of significant renal failure mayprohibit infusion of sufficient volume.The initial response to plasmapheresisusually is excellent. Relapse occurs inapproximately 30% of HIV-uninfectedpatients and probably in a higher per-Figure 1. Schistocytes in blood from patient with thrombotic thrombocytopenic purpura.

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centage of HIV-infected patients. Anti-retroviral therapy, which is believed toremove the antigen drive for antibodyproduction, has been reported to reducethe rate of relapse in case studies.Steroids may also be helpful in thisregard. In refractory cases, other optionsinclude rituximab, anti-CD20 monoclon-al antibody, vincristine, azathioprine, andsplenectomy. Despite the severe throm-bocytopenia, platelet infusions are con-traindicated because they can fuel theintravascular clotting. Overall, survival isgreater than 90% if treatment is initiatedearly in patients receiving plasmaphere-sis, antiretroviral therapy, and adequatesupportive care.

Diffuse InfiltrativeLymphocytosis Syndrome

Diffuse infiltrative lymphocytosis syn-drome (DILS) is an autoimmune syn-drome characterized by the oligoclonalexpansion of CD8+ T lymphocytes in

response to HIV antigens. It is oftenaccompanied by lymphocytic infiltrationof the salivary glands, as well as of thevisceral organs. DILS may be seen in allstages of HIV infection; in one study of35 patients, 37% of whom had AIDS,diagnosis occurred at a mean CD4+ cellcount of 342/µL (range, 44-876/µL; Kaziet al, AIDS, 1996). The disorder appearsto be more common in populations withmajor histocompatibility complex (MHC)class 1 and 2 alleles consisting of humanleukocyte antigen (HLA)-DR5 and HLA-DRw6. HLA-DR5 and DILS are both morecommon in African Americans. It is esti-mated that patients with DILS are morethan twice as likely to be AfricanAmerican and 2.8 times more likely tohave acquired HIV via homosexual sexu-al contact than those without DILS.

Bilateral parotid gland enlargement,which occurs in approximately 90% to100% of cases, is the most common pre-sentation of DILS (Figure 2). Patientsoften have the associated symptoms ofdry mouth and dry eyes, similar to thatobserved in Sjogren syndrome but with-out anti-Rho or anti-La antibodies.Patients may have extremely high CD8+cell counts. In one study, the meanCD8+cell count was 1639/µL, with arange of 560/µL to nearly 5000/µL.Lymphocyte infiltration of extraglandularorgans is common (Table 1). Visceralinvolvement can include the lungs; 31%of patients presented with lymphocyticinterstitial pneumonitis in one study(Kazi et al, AIDS, 1996).

Patients may be asymptomatic orpresent with mild to moderate dyspneaon exertion. The pneumonitis is similarto other forms of pneumonitis observed

in HIV disease, making it important toperform a diagnostic bronchoscopy withbiopsy. Lymphocytic hepatitis may bemanifested as elevated liver enzymes butmay also progress to frank liver failure.Gastric involvement may need to be dif-ferentiated from gastric cancer orsyphilis. Peripheral neuropathy is com-mon and resembles HIV-associated neu-ropathy, although the neuropathy mayoccur at higher CD4+ cell counts inDILS. Next to effects in the lung, muscleinvolvement is most common, occurringin 26% of patients. Patients have elevat-ed serum creatine phosphokinase andcan have marked symptoms of myalgiaand muscle weakness, with the presenta-tion closely resembling polymyositis. Inaddition to a positive HIV test, diagnosisof DILS involves tissue diagnosis via labi-al salivary gland biopsy and other tissuebiopsies, including bronchoscopy withbiopsy and liver biopsy, as well as galli-um and computed tomography (CT)scans.

Patients with DILS usually do verywell from an HIV disease standpoint.Some data indicate a slower progressionof HIV disease in patients with DILS, pre-sumably as a result of the heightenedCD8+ cell response to the virus. Thegoal of treatment is to minimize damagedue to the exuberant lymphocyteresponse. High-dose prednisone can beused to decrease inflammation. The besttreatment is antiretroviral therapy, toremove the antigenic drive underlyingthe inflammatory response. An exampleof response of the condition to initiationof antiretroviral therapy is shown inFigure 2.

Castleman’s Disease

The following case illustrates some of thefindings in HIV-associated Castleman’sdisease.

A 33-year-old African American manwith AIDS, CD4+ cell count of 20/µL,was admitted to the hospital with feverand increasing abdominal fullness. Hehad been diagnosed with disseminatedMycobacterium avium complex infectionseveral weeks prior to admission andwas taking sulfamethoxazole/trimetho-prim, ethambutol, and clarithromycin.He had been unable to tolerate hisantiretroviral regimen of efavirenz,lamivudine, and zidovudine. He wastoxic and febrile and had massive hep-

Table 1. Visceral Involvement in DiffuseInfiltrative Lymphocytosis Syndrome

• Parotid involvement• Lung

– Lymphocytic interstitial pneumonitis • Gastrointestinal tract

– Lymphocytic hepatitis– Plastica gastric lymphocytic

infiltration—linitis • Nerve

– Cranial nerve palsies– Peripheral neuropathies

• Muscle– Inflammatory myositis

Figure 2. Patient with diffuse infiltrative lymphocytosis syndrome with characteristic bilater-al parotid gland enlargement (left) and after antiretroviral treatment (right).

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atomegaly and splenomegaly. Laboratoryresults showed platelet count of 83,000/µL, hemoglobin 7.5 gm/dL, and lactatedehydrogenase 497 U/L. CT scansshowed shotty hilar adenopathy in thelungs, massive hepatosplenomegaly inthe abdomen, and scattered smallmesenteric lymph nodes. Liver biopsywas normal, and bone marrow biopsyshowed no granulomas, fungal elements,or lymphoma. The patient underwentlaparotomy with splenectomy. At laparo-tomy, 3 celiac nodes were removed, withhistology being consistent with hyalinevascular Castleman’s disease. Thepatient defervesced and was started onefavirenz, stavudine, and lamivudine. Hecontinues to do well 2 years later. This,however, is not the typical outcome ofthe disease.

Castleman’s disease is a lymphoprolif-erative disorder seen in HIV-infected andHIV-uninfected patients. It presents withadenopathy, hectic fevers, splenomegaly,hepatomegaly, and polyclonal gam-mopathy. It can occur as 2 clinical syn-dromes. Localized Castleman’s disease ismore common in HIV-uninfected individ-uals. It may be asymptomatic or it maybe associated with symptoms caused bycompression of organs by the largelymph node mass. Multicentric disease ismore common in HIV-infected patients.It is characterized by numerous en-larged, usually peripheral, lymph nodes;organomegaly; and systemic symptomssuch as hectic fever. Lab abnormalitiesinclude thrombocytopenia and anemia.The 2 histologic variants of Castleman’sdisease are the plasma cell form and thehyaline vascular form (Figure 3). Thehyaline vascular form is more common

in localized Castleman’s disease than theplasma cell form; the 2 variants maycoexist.

Castleman’s disease is highly associat-ed with HHV-8, which is found in 100%of HIV-infected Castleman’s diseasepatients and in 40% of HIV-uninfectedCastleman’s disease patients. Exacerba-tion of Castleman’s disease is associatedwith increased HHV-8 viral load andappears to correlate with serum levels ofviral interleukin (IL)-6 levels (analogousand homologous with human IL-6).Treatment for localized Castleman’s dis-ease is excision of the affected nodes,which is associated with good prognosis.Treatment for multicentric Castleman’sdisease is not well established, and prog-nosis remains poor in patients with thisform. Steroids, rituximab, and chemo-therapy have been used in multicentricdisease, but no consistent responseshave been observed. Antiretroviral thera-py does not consistently alter the courseof the disease. Treatments under investi-gation include a humanized antibody toIL-6 receptor.

The noninfectious syndromes dis-cussed above are not common, but theycan mimic more common HIV-associat-ed diseases. Recognizing these syn-dromes can not only limit unnecessaryworkup and treatment, but in somecases, such as TTP, can be lifesaving.

Presented in March 2005. First draft pre-pared from transcripts by Matthew Stenger.Reviewed and updated by Dr Eaton in June2005.

Financial Disclosure: Dr Eaton has no affilia-tion with commercial organizations that may

have interests related to the content of thisarticle.

Suggested Reading

Kazi S, Cohen PR, Williams F, Schempp R,Reveille JD. The diffuse infiltrative lympho-cytosis syndrome. Clinical and immuno-genetic features in 35 patients. AIDS.1996;10:385-391.

Mehta NJ, Khan IA, Mehta RN, SepkowitzDA. HIV-Related pulmonary hypertension:analytic review of 131 cases. Chest.2000;118:1133-1141.

Recusani F, Di Matteo A, Gambarin F,D'Armini A, Klersy C, Campana C. Clinicaland therapeutical follow-up of HIV-associat-ed pulmonary hypertension: prospectivestudy of 10 patients. AIDS. 2003;17(Suppl1):S88-S95.

Torok TJ, Holman RC, Chorba TL. Increasingmortality from thrombotic thrombocy-topenic purpura in the United States--analy-sis of national mortality data, 1968-1991.Am J Hematol. 1995; 50:84-90.

Tsai HM. Advances in the pathogenesis,diagnosis, and treatment of thromboticthrombocytopenic purpura. J Am SocNephrol. 2003;14:1072-1081.

Zietz C, Bogner JR, Goebel FD, Lohrs U. Anunusual cluster of cases of Castleman’s dis-ease during highly active antiretroviral ther-apy for AIDS. N Engl J Med. 1999;340:1923-1924.


Figure 3. Histologic variants of Castleman’s disease. Left shows plasma cell form, characterized by interfollicular predominance of plasma cellspositive for CD138. Right shows hyaline vascular form, characterized by germinal centers with vascularization and an “onion skin” arrange-ment of mantle-cell lymphocytes. Reproduced with permission from Zietz et al, N Engl J Med, 1999.

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IntroductionThe relationship between a patient’s sexand that individual’s ability to tolerateantiretroviral drugs is increasingly beingexamined. Several lines of evidencesuggest that women are more likely thanmen to experience adverse effects ofantiretroviral drugs.1 Nevirapine, a non-nucleoside reverse transcriptase inhibitor(NNRTI), is associated with rash andhepatitis more frequently in womenthan men.2-6 Protease inhibitor (PI)-asso-ciated gastrointestinal intolerance andmetabolic disorders are also reportedmore frequently among women.7-10

Boxwell and colleagues11 reported that83% of 60 cases of lactic acidosis in HIV-infected patients treated with nucleosidereverse transcriptase inhibitors (nRTIs)involved women, and 85% of the 20 fatalcases were in women. Another study12

examined the relationship between sex

and lipodystrophy in 2258 HIV-infectedpersons on antiretroviral therapy andfound that morphologic alterations weretwice as likely in women. These obser-vations suggest that adverse effects maybe more frequent in women than inmen receiving antiretroviral therapy.

It has been generally presumed thatthe efficacy of an antiretroviral drug iscomparable in men and women. Howev-er, 3 recent studies suggest that this maynot always be the case. One study fromthe United Kingdom13 evaluated the effec-tiveness of potent antiretroviral therapyin 91 women and 366 men. Virologic sup-pression was achieved more rapidly inwomen, and the response was moredurable. A second study14 evaluated sexdifferences in the clinical response toantiretroviral therapy in 497 men and146 women who were observed formore than 13 months. Disease progres-sion occurred in 11% of men and in 8%of women. Hospital admission for anAIDS-defining illness was required for17% of the men and 12% of thewomen. A third study,9 involving 78women and 616 men, found that theefficacy of antiretroviral therapy inreducing the plasma HIV-1 RNA concen-tration was similar for men and women;however, the mean increase in the CD4+cell count was greater in women (116/µL)

than in men (84/µL). Although these stud-ies need to be corroborated, the findingssuggest that sex may influence the phar-macologic effects of the antiretroviraldrugs. Data that indicate increasedadverse effects and possibly greater effi-cacy suggest that women may have bet-ter virologic responses to comparabledrug doses than do men, or that womenmay experience higher serum or tissuedrug concentrations.

Mechanisms proposed to explain sexdifferences in drug effects have includedphysiologic differences in factors suchas total body weight, fat distribution, pro-tein binding, gastric motility and acidsecretions, glomerular filtration rates, andthe influence of sex hormones on drugmetabolism. More recently, however,there is growing evidence to suggest thatthe mechanism of sex-related differencesin drug effects may occur at the molecu-lar level. Sex-related variations in theexpression and activities of drug trans-porter genes, proteins, and enzymesinvolved in phase 1 and 2 biotransforma-tion that form the xenobiotic cascademay underlie some of the observed dif-ferences between men and women inresponding to certain drugs. This reportexamines how differences in the expres-sion and activities of these importantdrug-disposing molecules may explainsome of the sex-related differencesreported in association with the effects ofthe antiretroviral drugs.

Antiretroviral Drug Transporters

The drug transporter P-glycoprotein (Pgp)is an important component of the xenobi-otic cascade that influences the bioavail-ability of drugs. Pgp is encoded by thehuman multidrug resistance (MDR1) geneand is constitutively expressed in epithe-lial cells, especially in tissues importantfor drug disposition, such as the apicalsurfaces of intestinal enterocytes, hepato-

Sex Differences in the Pharmacologic Effects ofAntiretroviral Drugs: Potential Roles of Drug Transporters and Phase 1 and 2 Metabolizing EnzymesIghovwerha Ofotokun, MD, MSc

Sex differences in the pharmacologic effects of antiretroviral drugs are increasing-ly being reported. Emerging evidence suggests that women may be at increased riskof developing adverse effects of antiretroviral drugs. Several mechanisms havebeen proposed to explain sex differences in drug effects, including physiologic dif-ferences between men and women and the influence of sex hormones on drugmetabolism. This article reviews sex-related variations in the levels of expressionand activities of drug transporters and metabolizing enzymes involved in the dis-position of the antiretroviral drugs, and postulates that these variations may part-ly explain sex differences in the responses to these drugs. Studies that explore rela-tionships between levels of expression and activities of relevant enzymes and drugtransporters and observed sex-related differences in treatment responses toantiretroviral drugs will help clarify the extent to which molecules involved in drugdisposition affect sex differences in treatment response.

Author Affiliation: Department ofInternal Medicine, Division of InfectiousDiseases, Emory University School ofMedicine, Atlanta, GA. Send correspon-dence to Ighovwerha Ofotokun, MD,Department of Internal Medicine, Divisionof Infectious Diseases, Emory UniversitySchool of Medicine, 69 Jesse Hill Sr. Drive,Atlanta, GA 30303. Phone: 404-616-0659;e-mail: [email protected].

Review

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cytes, and proximal renal tubular cells.15

Expression of Pgp by these tissuesreduces drug absorption from the gas-trointestinal tract and enhances drugelimination into bile and urine.16 Becauseof the key role played by Pgp in drug dis-position, sex-mediated differences in itsexpression and activities could result indifferences between men and women inthe pharmacologic activities of drugstransported by this molecule.

Recent observations indicate thatPgp influences the disposition ofantiretroviral drugs, particularly HIV PIs.Using L-MDR1 and Caco 2 cell lines thatoverexpress Pgp, Kim and colleagues17

demonstrated that indinavir, nelfinavir,and saquinavir are transported by Pgp.They also showed that the plasma con-centrations of these drugs after oraladministration were 2- to 5-fold higherin mdr1a knockout mice than in wild-type mice. Another study18 showed thatthe transport of saquinavir and ritonavirwas 3 times lower across a monolayer ofPgp-enriched Calu-3 cells derived fromhuman airway epithelium than across asimilar layer of cells with little Pgp.Several other studies using in vitro mod-els, such as Caco-2 or MDR1-transfectedLLC-PK1 cells, have shown that HIV PIsexhibit directional transport.19,20 In addi-tion, Pgp inhibitors such as LY-335979,cyclosporin, and verapamil, block cellu-lar transport of HIV PIs, confirming thatthe PIs are substrates for Pgp.21 The reg-ulatory role of drug transporters in thedisposition of the HIV nRTIs has not beenextensively studied. However, data from2 studies indicate that the multidrugresistance proteins MRP4 and MRP5may efflux monophosphate metabolitesof nucleoside analogues such as nRTIsfrom cells.22,23

Given the role of drug transporters inthe bioavailability of antiretroviral drugs,in particular the PIs, factors that regulatethe expression of these transportersmight influence responses to thesedrugs. Data from animal models andhuman studies suggest that sex mayplay a role in the expression of Pgp andother drug transporters. One example ofsuch evidence was provided by Schuetzand colleagues,24 who evaluated theexpression of Pgp by hepatic cells in 41subjects and found that Pgp activityamong women was only one third toone half that of men. In another study,involving 36 men and 25 women with

B-cell chronic lymphocytic leukemia,Steiner and colleagues25 showed thatwomen were almost 2 times less likelythan men to be positive for the MDR1genotype that encodes for Pgp expres-sion. Sex differences in Pgp expressionhave also been demonstrated in rats26

and Chinese hamsters.27 Sex-dependentexpression has been described for othertransporters, including sodium tauro-cholate cotransporting polypeptide(NTCP)28 and the organic cation trans-porter 2 (OCT2).29 These observed lowerexpressions of Pgp in women suggestthat women might be more likely thanmen to achieve higher cellular and tissueconcentrations of antiretroviral drugs thatare Pgp substrates. This may partiallyexplain the increased frequency andseverity of adverse reactions and perhapsthe enhanced efficacy of some of thesedrugs in women compared with men.

Antiretroviral MetabolizingEnzymes

Other important components of thexenobiotic disposition pathway that limitthe bioavailability of drugs are the drug-metabolizing enzymes. The cytochromeP450 (CYP450) superfamily of enzymesaccounts for more than 95% of thephase 1 metabolism of all drugs.30 TheCYP450 system consists of at least 11families of enzymes, of which 3 (CYP1,CYP2, and CYP3) are important inhumans. The liver is the primary site ofCYP450 activity, but CYP3A is also pre-sent in the gastrointestinal enterocytes.CYP3A is the most abundant CYP450enzyme in the human liver and isresponsible for the metabolism ofapproximately one half of all drugs thatundergo phase 1 hepatic metabolism.Phase 2 pathways in drug metabolisminclude conjugation reactions, such asglucuronidation, sulfation, acetylation,methylation, and glutathione conjuga-tion.

All currently approved HIV PIs aremetabolized by CYP450 isoforms.Fitzsimmons and Collins31 demonstrat-ed the in vitro biotransformation ofsaquinavir by intestinal and hepaticmicrosomes to multiple hydroxylatedderivatives and also showed thatCYP3A4 was the main enzyme involvedin the biotransformation. CYP3A4 is alsoresponsible for the metabolism of indi-navir,32 amprenavir,33 nelfinavir,34 and

lopinavir.35 Ritonavir is metabolized pri-marily by CYP3A4 and, to a lesserextent, by CYP2D6 and CYP2C9.36

The CYP450 enzyme system is alsoresponsible for the biotransformation ofthe NNRTIs. In vitro studies of nevirap-ine biotransformation have demonstrat-ed that the isoenzymes CYP2B6 andCYP3A4 metabolize nevirapine, withCYP2D6 playing a minor role.37 Theisoenzyme primarily responsible for thebiotransformation of efavirenz is CYP2B6,with some involvement by CYP3A4.38

Delavirdine is metabolized primarily byCY3A4 and, to a lesser extent, byCYP2D6.39 Many PI and NNRTI metabo-lites generated by CYP450 biotransfor-mation subsequently undergo phase 2reactions before being eliminated inurine or bile.

The nRTIs, on the other hand, areeliminated unchanged in the urine, orundergo hepatic glucuronidation prior toexcretion in urine or bile.40-44 Changesin plasma concentrations of the nRTIs,however, may be of less clinical rele-vance than for PIs and NNRTIs, becausetheir antiviral effects mainly depend onthe rate and extent of intracellular phos-phorylation by cellular kinases intotriphosphate derivatives.45 The intracel-lular accumulation of nRTI mono- ordiphosphates resulting from rate-limit-ing steps in this phosphorylation path-way could be responsible for some ofthe toxic effects of the drugs, particular-ly within mitochondria.46

Knowledge is growing about sex dif-ferences in regulating the expression andactivity of phase 1 and phase 2 drug-metabolizing enzymes, which are proba-bly related to endogenous sex hor-mones.47 Activities of CYP1A2 andCYP2E1 may be higher in men than inwomen,48-51 whereas CYP2D6 activitymay be higher in women than in men.52

Sex differences in CYP2C19 activityappear to show ethnic variations:CYP2C19 activity is higher in Chinese,Jewish-Israeli, and African Americanwomen than in men of these ethnicbackgrounds.53-55 No sex difference inthe activity of CYP3A seems to exist.56

Although hepatic clearance of drugs thatare substrates for both CYP3A and Pgp(such as erythromycin and verapamil)appears to be higher in women than inmen, this may be explained largely bylower hepatic Pgp activity in women.57-59

The activities of some phase 2 isoen-

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zymes also exhibit sex differences.Thiopurine methyltransferase (TPMT)activities are 14% lower in liver tissuesfrom women than from men.60 Similarly,levels of catechol-O-methyltransferaseactivity are lower in women.61 The activ-ity of several isoenzymes of the uridine5-diphosphate glucuronosyltransferase(UGT) superfamily, including UGT1A1,UGT1A6, UGT1A8, UGT1A9, andUGT1A10, is also lower in women.62-65 Astudy from Finland shows that phenolsulfotransferase activity is more than60% lower in women than men.65 Sexdifferences in regulation of the activitiesof the cellular kinases that activate nRTIsremain undefined.

Based on available studies, enzymesinvolved in phase 1 reactions may haveonly a limited role, if any, in the sex-related differences in pharmacologiceffects of the antiretroviral drugs. Theactivity of CYP3A, the principal isoformof the CYP450 system, in the biotrans-formation of PIs and NNRTIs does notappear to be influenced by sex. AlthoughCYP2D6 activity is reported to be higherin women than in men, the role of thisisoform in the metabolism of ritonavirand delavirdine is limited. In contrast,activities of many isoenzymes involvedin phase 2 reactions are lower in womenthan in men, suggesting that antiretrovi-ral agents (or their metabolites) thatundergo biotransformation by thesepathways may reach higher concentra-tions in the cells and tissues of femaleHIV patients than in male patients.

Sex differences in the activities ofcellular kinases that activate nRTIsremain unclear. Studies to explore sexdifferences in the expression and activi-ties of these key enzymes in themetabolism of the nRTIs will be of inter-est for 2 reasons. First, there are docu-mented sex differences between menand women in the development ofadverse effects associated with thenRTIs, in particular, lactic acidosis.Second, both the efficacy and the toxiceffects of the nRTIs are related to thephosphorylated products of the cellularkinases.

Conclusion

HIV infection has become a chronic,treatable illness, especially in the devel-oped countries, as many HIV-infectedpatients are on antiretroviral therapy and

are living longer. The adverse effects ofthese drugs, particularly in women, are agrowing source of concern, becausemany observational studies have shownthat women experience greater toxiceffects with all classes of antiretroviraldrugs. Although sex differences in theeffects of these drugs may be due in partto physiologic and hormonal differencesbetween men and women, variations inthe activities of drug transporters andmetabolizing enzymes involved in phase1 and 2 reactions may also be involved.Further studies are needed to relateactivities of these enzymes and drugtransporters and observed sex differ-ences to the effects of the antiretroviraldrugs. Such studies will enhance our abil-ity to develop new agents that are bettertolerated by both sexes, and to identifydrug dosages that are most effective forwomen.

Financial Disclosure: Subsequent to thesubmission of this article, Dr Ofotokunreceived research funding from Abbott,Pfizer, and ViroLogic.

Acknowledgement: The author acknowl-edges Flo Witte for her editorial review ofthe manuscript.

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