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Infectious Diseases in Obstetrics and Gynecology 6:197-203 (1998)(C) 1998 Wiley-Liss, Inc.

Zidovudine

R. Sperling*Department of Obstetrics, Gynecology, and Reproductive Sciences, The Mount Sinai Medical Center,

Newa York, NY

KEY WORDS

antiretroviral regimens; HIV-1 infection; mother-to-child HIV-1 transmission

idovudine (RetrovirTM) is one of the bestknown agents used in the treatment of women

with human immunodeficiency virus type-1 (HIV-1) infection. This generally well-tolerated agenthas become a mainstay for the prevention ofmother-to-child HIV-1 transmission and is often a

component of combination antiretroviral regimensutilized for the treatment of both adult and pedi-atric HIV-1 infected individuals.

STRUCTURE AND DERIVATION

Zidovudine (ZDV,AZT, 3’-azido-3’-deoxy-thymidine) is a synthetic nucleoside analogue of a

naturally occurring nucleoside, thymidine, in whichthe 3’-hydroxy (-OH) group is replaced by an azido(-N3) group (Fig. 1).

MECHANISM OF ACTION

Zidovudine (ZDV,AZT) is one of a class of humanimmunodeficiency virus type-1 (HIV-1) antiviral

agents known as dideoxynucleoside reverse tran-

scriptase inhibitors (NRTIs). ZDV inhibits HIV-1reverse transcriptase, the enzyme needed to cata-

lyze the synthesis of proviral double-strandedDNA from the RNA template (Fig. 2), and there-fore interferes with a critical step in the HIV virallife cycle. The antiviral activity of ZDV dependson the intracellular conversion of the drug to a tri-phosphate metabolite and requires intracetlularhost cell kinases for conversion to this active 5’-triphosphate form. The active 5’-triphosphate hasan affinity for HIV reverse transcriptase and com-

petes with endogenous triphosphate nucleotides

for incorporation into the newly synthesized pro-viral DNA. ZDV triphosphate lacks a free 3’-hy-droxyl group. In order for nucleic acid replication to

occur, the 3’-hydroxyl of a naturally occurringnucleoside is the acceptor for covalent attachmentof subsequent nucleosides 5’-monophosphate.When ZDV triphosphate is incorporated, it acts as

a chain terminator preventing further elongation ofthe viral DNA chain.

In addition to ZDV, the other NRTIs that are

approved by the Food and Drug Administration(FDA) are didanosine (ddi), zalcitibine (ddC),stavudine (d4T), and lamivudine (3TC). Althoughthe structure and mechanism of action of all thenucleoside analogues are similar, they differ signifi-cantly in their intracellular phosphorylation path-ways and kinetics, which contribute to differencesin their in vitro antiretroviral activity and pattern oftoxicities. The NRTIs have a wider spectrum ofantivirat activity than the other available HIV-1 an-

tiviral agents. Other classes of antiviral agents thathave been approved by the FDA for the treatment

of HIV disease are non-nucleoside reverse tran-

scriptase inhibitors (NNRTIs), which include ne-

virapine and delaviridine, and the HIV protease

inhibitors which include ritonavir, saquinavir, indi-

navir, and nelfinavir. HIV protease inhibitors have

greater activity than either NRTIs or NNRTIsagainst HIV-1; these compounds were specificallydesigned based on the ,structure of the HIV prote-

ase enzyme and have a spectrum of activity limitedto HIV-1 and to a lesser extent HIV-2.

*Correspondence to: R. Sperling, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, The Mount SinaiMedical Center, Box 1173, One Gustave L. Levy Place, New York, NY 10029-6574. E-mail: [email protected]

Antimicrobial SymposiumReceived 24 August 1998

Accepted 14 October 1998

ZIDOVUDINE SPERLING

HN "AXcHHOCH

Fig. I. Structure of zidovudine (ZDV,AZT, 3’-azido-3’-deoxythymidine).

PHARMACOKINETICS

Zidovudine is rapidly absorbed by the gastrointes-tinal tract following oral administration with peakserum concentrations occurring within 0.4-1.4hours. Absorption shows considerable interindivid-ual variation and is influenced by the time andcontent of the last meal. Once absorbed, prior to

systemic distribution, zidovudine undergoes sig-nificant first-pass metabolism, giving an averagebioavailability of 63%. Zidovudine is approxi-mately 25% protein bound, primarily to albumin.Zidovudine distributes into cells by passive diffu-sion and is relatively lipophilic; it can be detectedin fluids other than plasma, which contributes to itslarge distribution volume. Zidovudine is primarilymetabolized by liver through hepatic 5’-gluc-uronidation, forming a stable glucuronidated me-

tabolite (GZDV) that is excreted by the kidneys.Approximately 14-20% of unchanged drug and 60-70% of its major metabolite are excreted in theurine following oral or intravenous administration.

Administration of the same standard dose of oralzidovudine results in a variable plasma concentra-

tion among adults. The variability is a consequenceof between-patient differences in the absorption,distribution, metabolism, and clearance of thedrug. Although the plasma pharmacokinetic char-acteristics have been well studied, the therapeuticrange of ZDV and the importance of intracellularpharmacokinetics are not completely understood.Therefore, the optimal dosing strategy for ZDV hasnot been determined. Recommended doses (seeTable 1) are based on clinical endpoints, and not

on pharmacodynamic considerations.

Pharmacokinetics in pregnancy have been stud-ied.z-4 ZDV and GZDV have been detected in thefetus, amniotic fluid, and breast milk. Transplacen-tal transfer of ZDV is by passive diffusion,s there-fore, maternal plasma concentrations will be a ma-

jor determinant of fetal concentrations.6,7 Preg-nancy introduces additional sources of variability inthe plasma drug concentration, including changesin volume of distribution (expanded plasma vol-ume, increased adipose tissue and the addition of a

fetal compartment), changes in drug clearance (in-crease in cardiac output and a concomitant increasein renal blood flow), and increases in hepatic me-

tabolism. Preliminary reports of zidovudine dispo-sition in obese pregnant women found that achiev-able plasma concentrations were far lower than ex-

pected based on population pharmacokineticinformation.8 In addition, information from theAIDS (acquired immunodeficiency syndrome)Clinical Trial Group (ACTG) 076 study suggeststhat maternal obesity may be a risk factor for thefailure of ZDV prophylaxis to prevent perinatalHIV-1 transmission. (R. Sperling, personal commu-nication)

CLINICAL APPLICATIONS(DEMONSTRATED EFFICACY)Treatment of Adult Patients

Zidovudine has been extensively studied in thetreatment of patients with HIV infection whoseCD4+ cell counts are -<500 cells/mm3. In initialstudies, ZDV reduced the risk of disease progres-sion, opportunistic infections, and death in patientswith advanced HIV disease.9 Further experiencewith the drug revealed that the clinical benefits ofZDV monotherapy were not sustained over thelong term. Recent studies have shown that the useof ZDV as part of a combination antiretroviral regi-men results in suppression of viral replication andgreater clinical benefits, including survival out-

come, when compared with ZDV alone.1

Prevention of Mother-to-Child HIV-ITransmission

In February 1994, the National Institutes of Health(NIH)-sponsored ACTG 076 study was closed to

enrollment and unblinded when an interim analy-sis demonstrated that a regimen that combined ma-

ternal and newborn ZDV could dramatically reducethe risk of mother-to-infant HIV-1 transmission.1

198 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY

ZIDOVUDINE SPERLING

HIV

CD4Receptor

Site of actionfor reversetranscriptaseinhibitors

MatureVirion

BuddingParticle

0 OsGenomic RNA /’_ Processing

, and

Reverse Transcriptasea Host 7_//Chromosomec-DNA UOUDle // /

DNA // stranded iI% [[circularized DNA%" Proviral

UnintegratedDNA

DNA

Unintegrated

GlycoproteinKnobs

Site of actionfor proteaseinhibitors

Fig. 2. Life cycle of HIV.

The availability of a regimen that could reduce thetransmission of a fatal pediatric disease led theUnited States Public Health Service lz to developconsensus guidelines for clinicians about the use ofZDV during pregnancy. Since implementation ofthese guidelines, additional information about theefficacy of ZDV for the prevention of perinataltransmission has become available.

In November 1996, an efficacy update from theACTG 076 study confirmed the interim findings.The original report was a Kaplan-Meier estimate ofthe transmission risk and was based on 363 mother-infant pairs. The recent update included 402mother-infant pairs, all ofwhom had completed the18-month infant follow-up; the rate of HIV-1 trans-

mission was 7.6% with ZDV treatment and 22.6%with placebo (P < .001). 1"

In March 1997, enrollment in another pediatricACTG study, Protocol 185, was stopped due to an

unexpectedly low transmission rate in both studyarms. lz The ACTG 185 was a randomized, con-

trolled clinical trial which compared HIVIG (an im-munoglobulin preparation containing high levels ofantibodies to HIV) to IVIG (standard immunoglob-

ulin) to determine whether HIVIG could furtherreduce the risk of mother-to child transmission if itwas added to the maternal-child ZDV regimen suc-

cessfully utilized in ACTG 076. The ACTG 185study was designed for women with more advancedimmunosuppression than the 076 study. In ACTG076, all women had CD4+ T-cell counts exceeding200 cells/mm3, and only 5% had received any priorZDV; in contrast, in ACTG 185, 23% had baselineCD4+ cell counts less than 200 cells/mm3, and 21%of women had received prior ZDV. After analyzingoutcomes in 379 infants, the estimated overall rate

of mother-to-infant HIV transmission was 4.8%with no difference between HIVIG and IVIG re-

cipients. 14 The utility of prophylactic ZDV in preg-nant women with advanced immunosuppressionthat was demonstrated in ACTG 185 is consistentwith other reports. s,16

In February 1998, enrollment in a trial con-ducted by the Ministry of Public Health of Thai-land (in collaboration with the Centers for-DiseaseControl and Prevention [CDC]) was stopped whenan interim analysis demonstrated the success of a

short-course of maternal antepartum/intrapartum

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 199

ZIDOVUDINE SPERLING

TABLE I. Zidovudine dosing considerations

Mode of DosageMedication action form Dosing

Major Drug Pregnancytoxicities interactions considerations

Zidovudine(AZT, ZDV,Retrovir)

Nucleosidereverse

transcriptaseinhibitor

(NRTI)

100 mg capsules300 mg tabletsSyrup: 50mg/ml IV: 10mg/ml

Also available incombinationwith 3TC(Combvir-AZT300 mg/3TC150 mg)

Adults:100 mg orally 5times per day(dose studiedin perinatalpreventiontrials)

200 mg orally 3times per day

300 mg orallytwice a day

Intravenous in

labor: 2 mg/kgloading dose,followed bycontinuous

infusion ofmg/kg/hr

Intravenousnewbornintermittent

infusion: 1.5 mg/kgevery 6 hours

Pediatrics:90-180 mg/ma

orally every6-12 hr

Specialconsiderations:Dose interruption

for severeanemia or

granulocytopenia

Most frequent: Co-administration Category: CBone marrow with

suppression ganciclovir, Transplacental(anemia and alpha-interferon, passage: yesgranulocytopenia) dapsone,

flucytosine, or Animal safety: highNausea, myalgias, vincristine can doses during

headaches, and increase late gestationinsomnia are hematologic associated with

common and toxicity transplacentaldiminish over carcinogenicitytime Phenytoin and in mice

fluconazole can

Less frequent: effect ZDV Human safety:Long-term levels extensive

administration experience;has been reversible

associated with anemia in the

peripheral newborn;

myopathy long-termsafety is beingstudiedMarked elevations

in liver functiontests,

hepatomegaly,and lacticacidosissecondary to

steatosis hasbeen reported

Follow-up ofchildren

exposed inutero is

recommended

zidovudine therapy for the prevention of mother-to-child HIV-1 transmission. 17 When ZDV, 300 mgtwice daily, was given from 36 weeks of gestationuntil the onset of labor and then increased to 300mg orally every three hours in labor, the transmis-sion rate was decreased by 51%;. the Kaplan-Meierestimates of transmission risk were 9.2% in the pla-cebo group and 18.6% in the placebo group, P0.008. These findings are consistent with observa-tional studies in the United States ls,16 and providesubstantial scientific support for using shortercourses of zidovudine when the complete 076 regi-men cannot be given.

Results of all three clinical trials are consistentwith the mounting epidemiologic evidence sup-porting the use of ZDV regimens to preventmother-to-child HIV-1 transmission:

TABLE 2. Zidovudine regimen studied in

ACTG O76

Antepartum Intrapartum Newborndose dose dose

I00 mg orally 5 2 mg/kg loading 2 mg/kg orally everytimes a day, dose, followed hours, initiatedinitiated between by continuous within 8-12 hours

14 and 34 weeks infusion of of birth andof gestation and mg/kg/hr continued for 6

continued until weekslabor

Nationwide, the number of cases of pediatricAIDS reported to the CDC declined 47% be-tween 1992 and t996.18In North Carolina, mother-to-child transmissionrates have decreased from 21% in 1993 to 6% in1996 following the use of ZDV. 19


ZIDOVUDINE SPERLING

In New York City, in a cohort of 898 childrenfollowed between July of 1994 and June of 1996,the transmission rate was 13% in those mother-infant pairs who received any ZDV, comparedwith 26% in mother-infant pairs who received noZDV.z

In New York State, an observational study of 943HIV-exposed infants born after August 1995found a transmission rate of 6.3% among infantsexposed to the full 076 regimen, an 11.5% trans-

mission rate among infants expensed to ZDVstarting either in labor or in the immediate neo-natal period, and a 26.5% transmission rate

among infants who received no ZDV prophy-laxis, zl This is the first report that supports theefficacy of intrapartum/newborn regimens andeven newborn regimens alone if initiated within48 hours of birth.

ZDV MECHANISM OF ACTIONAS CHEMOPROPHYLAXIS

At the time of the interim ACTG 076 study analy-sis, the mechanism by which ZDV reduced the riskof transmission was unknown. 11 It is now known,through analysis of viral loads in maternal plasmasamples from entry and delivery, that ZDV appearsto act primarily by a mechanism other than thereduction of maternal viral burden. Neither thechange in maternal plasma viral load from entry to

delivery nor a critical level at delivery fully ac-

counts for the substantially reduced transmissionrate observed in the ZDV treated group. The pos-sibility of a significant prophylactic effect in utero

and/or intrapartum (both during and after expo-sure) has been raised.

Side Effects

Drug Toxicities in Adult Trials

Early studies utilizing 1200 mg/d reported signifi-cant patient problems with drug-associated toxici-ties. Later studies demonstrated the efficacy of500-600 mg/d with significantly reduced toxicity.The major side effects include anemia and/orgranulocytopenia, headache, fatigue, malaise, nau-

sea, and other gastrointestinal discomforts. Long-term ZDV therapy has been associated with myop-athy and rare cases of hepatic steatosis and lacticacidosis.

Drug Toxicities in Perinatal Transmission Trials

There remains ongoing concerns about the safetyof the 076 regimen, both for the mother and for theinfant. Specific questions have been raised regard-ing adverse effects of this regimen on the long-term health of uninfected infants and on maternaldisease progression.The only infant toxicity associated with the

ACTG 076 regimen has been a mild, reversibleanemia whose nadir has been at 6 weeks of agewith resolution by 12 weeks of age. Infant anemiawas not associated with the duration of maternalzidovudine treatment. Among uninfected infantsin the ACTG 076 study, there were no differencesbetween the zidovudine-exposed infants and theplacebo infants in growth patterns, immunologicparameters (lymphocyte subsets), or the occur-

rence of childhood neoplasias,zz The AntiretroviralPregnancy Registry, a collaborative prospectiveregistry supported by pharmaceutical manufactur-ers, has not found an association between ZDVexposure and congenital anomalies among thecases that have been reported to date.e3

There is no standard battery of safety tests inanimals that are required before a drug is approvedby the FDA for use in humans. Although animaltesting is frequently performed to assess pregnancysafety, animal data may be difficult to interpret andmay not accurately predict risks to human preg-nancy. Safety concerns about the use of ZDV inpregnancy have included concerns about poten-tial transplacental carcinogenicity. Theoretically,nucleoside analogs such as ZDV can interfere withDNA synthesis and are potential carcinogens. Inone rodent model, high doses of zidovudine givenduring pregnancy were not associated with adverseoutcomes in offspring, including the developmentof tumors,z4 In another model, extremely highdoses of zidovudine administered during preg-nancy were associated with an increased risk oftumors in offspring,zs An NIH panel comprised ofclinicians, scientists, and patient advocates re-viewed all available animal data and unanimouslyconcluded that the benefits of zidovudine in reduc-ing perinatal HIV far outweighed the potentialrisks. Other recommendations of this panel in-cluded the need to inform women of these data, to

conduct long-term follow-up on all children ex-


ZIDOVUDINE SPERLING

posed in-utero to ZDV, and to conduct more clini-cal and basic research on the topic.

In ACTG 076, at 6 months postpartum, therewere no differences in clinical, immunologic, or vi-rologic disease progression between those womenwho received the 076 ZDV regimen and those whoreceived placebo.2

ZDV Resistance

Monotherapy with antiretroviral agents has beenassociated with drug resistance. Drug resistance ismore likely to emerge with increasing duration oftherapy and with advancing immunosuppression.In the ACTG 076 study, maternal therapy was not

associated with the development of high level zid-ovudine resistance,z6

ZDV is available in a variety of different formula-tions (Table 1). Based on average wholesale prices,the unit cost of the 100-mg capsule is $1.59, theunit cost of the 300-mg tablet is $4.78, and the unitcost of a 200-mg bottle for intravenous injection is$17.30. Cost-effectiveness analyses have estimatedthat the ZDV drug cost per treated case followingthe ACTG 076 regimen is $895.z7

SUMMARY

Zidovudine was the first agent approved for treat-

ment of HIV disease, and since its widespreadavailability in 1987, the pharmacokinetic disposi-tion and clinical effects of ZDV have been exten-

sively evaluated. In addition to its utility as a com-

ponent of a multidrug combination regimen for thetreatment of adult and pediatric HIV-1 infection, itis the only agent approved by the FDA for theprevention of mother-to-child HIV-1 transmission.The effectiveness of ZDV for the prevention of

mother-to-child HIV-1 transmission has been dem-onstrated in several studies. The optimal time dur-ing gestation to initiate ZDV therapy and the rela-tive importance of the intrapartum and newborncomponents is the focus of both current interven-tional and observational studies. Until more infor-mation is available from these trials, the combinedmaternal/newborn ZDV regimen studied in ACTG076 remains the recommended treatment regimenof choice in the United States.

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ZIDOVUDINE SPERLING

16. Matheson PB, Abrams EJ, Thomas PA, et al.: Efficacyof antenatal zidovudine in reducing perinatal transmis-sion of human immunodeficiency virus type 1. J InfectDis 172:353-358, 1995.

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