NEUROLOGICAL AND DEVELOPMENTAL EFFECTSOF HIV AND AIDS IN CHILDREN

AND ADOLESCENTS

Wendy Mitchell*Childrens Hospital Los Angeles, Los Angeles, California

HIV-related encephalopathy is an important problem in verticallyinfected children with HIV. Infected infants may manifest early, catastrophicencephalopathy, with loss of brain growth, motor abnormalities, and cog-nitive dysfunction. Even without evidence of AIDS, infected infants scorelower than serorevertors on developmental measures, particularly languageacquisition. Children with perinatal or later transfusion-related infectiongenerally are roughly comparable developmentally to their peers until late intheir course. Symptoms similar to adult AIDS dementia complex are occa-sionally seen in adolescents with advanced AIDS, including dementia, bra-dykinesia, and spasticity. Opportunistic CNS infections such as toxoplasmo-sis and progressive multifocal leukoencephalopathy are less common inchildren and adolescents than in adults. Increasing evidence suggests thataggressive antiretroviral treatment may halt or even reverse encephalopa-thy. Neuroimaging changes may precede or follow clinical manifestations,and include early lenticulostriate vessel echogenicity on cranial ultrasound,calcifying microangiopathy on CT scan, and/or white matter lesions andcentral atrophy on MRI. Differential diagnosis of neurological dysfunction inan HIV-infected infant includes the effects of maternal substance abuse,other CNS congenital infections, and other causes of early static encepha-lopathy. Initial entry of HIV into the nervous system occurs very early ininfection. The risk of clinical HIV encephalopathy increases with very earlyage of infection and with high viral loads. Virus is found in microglia andbrain derived macrophages, not neurons. The neuronal effect of HIV isprobably indirect, with various cytokines implicated. Apoptosis is the pre-sumed mechanism of damage to neurons by HIV. © 2001 Wiley-Liss, Inc.MRDD Research Reviews 2001;7:211–216.

Key Words: HIV; acquired immunodeficiency syndrome; encephalopathy;brain; infants; children; adolescents

HIV AND THE NERVOUS SYSTEM

Encephalopathy is a prominent feature of AIDS in children,and is much more frequent in children than in adults. Inadults, AIDS dementia complex is seen in very late stages

of disease, while in children, encephalopathy may be an earlyfinding [Mintz, 1994]. In vertically HIV infected children, en-cephalopathy is frequently an AIDS-defining illness [Cooper etal., 1998], preceding other opportunistic infections, and mayoccur while the child is not yet severely immunologically com-promised [Tardieu et al., 2000]. Surveillance studies have doc-umented that encephalopathy occurs in the first year of life inabout 4% of infants with HIV, and that encephalopathy con-tributes substantially to increased mortality and morbidity [Lo-bato et al., 1995].

The neurological presentation of HIV encephalopathy inchildren varies. Age at infection and mode of transmission

(vertical infection versus transfusion in infancy; transfusion ver-sus sexual transmission in older children and adolescents) areimportant determinants of both the risk for and the manifesta-tions of encephalopathy. HIV clinical manifestations in thechild’s nervous system have been generally subdivided into astatic encephalopathy and a progressive encephalopathy, but thisdistinction may be artificial. Characteristic features are loss ofbrain growth (microcephaly) or brain atrophy; motor abnormal-ities, primarily affecting lower extremity function, spasticity, andcognitive delays or mental retardation. Expressive language istypically affected much more severely than receptive language,and may be abnormal prior to any other findings [Wolters et al.,1995]. Dementia, clinically resembling the adult form (AIDSdementia complex) is a rare manifestation of late-stage AIDS inadolescents. There are multiple reasons to assume that the en-cephalopathy developing early in vertically infected childrendiffers in pathophysiology from that found in adults with ad-vanced AIDS.

The presence of encephalopathy itself is an indicator ofdisease severity and progression. Mortality is higher in childrenwith encephalopathy, particularly those with early onset [Lobatoet al., 1995; Rigardetto et al., 1999].

PATHOPHYSIOLOGYInitial entry of HIV into the nervous system occurs very

early in infection. In adult primary infection, aseptic meningitiscan be a very early manifestation, and may be one of the featuresof an early, possibly autoimmune-mediated illness at the time ofseroconversion. This manifestation has not been reported inyoung children. The risk of clinical HIV encephalopathy in-creases with very early age of infection and with high viral loads[Gurbindo et al., 1999]. In vertically transmitted HIV, advancedmaternal disease is a risk for encephalopathy in the infant,probably due to high maternal viral loads. In addition, maternalencephalopathy is a risk for encephalopathy in the infants,possibly due to transmission of strains of the virus with a greaterpredilection for the nervous system, or higher degrees of neu-rotoxicity [Velez Borras et al., 1998].

*Correspondence to: Wendy Mitchell, MD, Childrens Hospital Los Angeles, Neurol-ogy 82, 4650 Sunset Boulevard, B7, Los Angeles, CA 90027.E-mail: WMitchell@chla.usc.edu

MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIESRESEARCH REVIEWS 7: 211–216 (2001)

© 2001 Wiley-Liss, Inc.

Virus is primarily found in micro-glia and brain derived macrophages, notneurons. A variety of histologic tech-niques have been used to localize virusactivity in the brain, generally combiningpolymerase chain reaction and in situ hy-bridization [Takahashi et al., 1996]. Vi-rally infected microglia may enhance mi-gration of immune-activated macrophagesacross the blood brain barrier [Persidskyet al., 1999]. Neurotoxic macrophageproducts may include pro-inflammatorycytokines, chemokines, platelet activat-ing factor, arachidonic acid and its me-tabolites, nitric oxide, and viral structuraland regulatory proteins, which may, inturn, be neurotoxic as well [Xiong et al.,2000]. Circulating tumor necrosis factor(TNF) has been found to be elevatedin encephalopathic compared to non-encephalopathic children with AIDS,suggesting a toxic effect of systemic TNFupon central myelin [Mintz et al., 1989].

The neuronal effect of HIV isprobably indirect. Various cytokineshave been implicated [Griffin, 1997].Several cytokines, elevated in the CSF ofpatients with HIV encephalopathy, havebeen demonstrated to promote apoptosis.Apoptosis is the presumed mechanism ofdamage to neurons by HIV. Infected mi-croglia and brain macrophages may ex-press pro-apoptotic enzymes that indi-rectly cause neuronal loss. Caspase-3, apro-apoptotic enzyme, has been found tobe upregulated in neurons, microglia,and macrophages in brain of patientswith HIV-1 progressive encephalopathy[Gelbard et al., 1997; 1998; James et al.,1999]. Components of the virus itself arethought to be neurotoxic, including theglycoproteins gp120 and gp 41, whichare in the coat of HIV-1 [Rafalowska,1998].

As with many neurologically dam-aging agents, excitotoxicty appears toplay a role in mediating cell death. AnHIV viral protein, gp120, acts in thepresence of macrophages as a toxin uponrat neurons. This effect is inhibited byN-methyl-D-aspartate (NMDA) block-ers as well as by calcium channel blockers[Lipton, 1991; Lipton et al., 1991; Lip-ton, 1994].

CLINICAL MANIFESTATIONSOF AIDS ENCEPHALOPATHY

Infants with clinically evidentAIDS encephalopathy often present withcatastrophic neurological illness, withrapid loss of developmental milestones,initial hypotonia followed by severe hy-pertonicity and hyperreflexia, failure ofbrain growth leading to microcephaly.The clinical picture is one of spastic di-

plegia or quadriplegia, with mental retar-dation, often most evident as loss of orlack of acquisition of expressive language.Receptive language may be relativelypreserved. With encephalopathy of earlyonset, the clinical picture may be indis-tinguishable from an encephalopathy dueto other prenatal or perinatal brain injury,including perinatal hypoxic-ischemic en-cephalopathy. Infants developing AIDSencephalopathy generally have very highsystemic viral loads, but may not haveother major manifestations of AIDS, suchas opportunistic infections or failure-to-thrive, at the onset of encephalopathy[Pollack et al., 1996]. Encephalopathymay be the AIDS-defining illness insome infants and young children. Earlyonset of encephalopathy is a clinical pic-ture virtually restricted to infancy. Forexample, Tardieu et al. [2000] comparedinfants enrolled in a perinatal cohortstudy to adults with known date of sero-conversion enrolled in a cohort study.They report that in the first year of in-fection, 9.9% of infants manifested en-cephalopathy, versus only 0.3% of adults.In the second year after infection, infantscontinued to have an increased incidenceof onset of encephalopathy (4.2% versus0% of adults). Subsequently, the rates ofonset of encephalopathy were about thesame, less than 1% per year in eachgroup.

Older children do not generallymanifest the rapidly progressive cata-strophic encephalopathy seen in infants.However, in children whose encepha-lopathy was arrested by aggressive anti-retroviral treatment, disease progressionmay be marked by substantial worseningof preexisting neurological signs andsymptoms. Irritability, inattention, loss oflanguage skills, worsening fine motorfunction, and onset of or worsening ofspasticity may be seen. Overt, severespastic quadriparesis or diplegia is rarewith disease progression, unless antiret-roviral treatment was started after therewas already some evidence of encepha-lopathy.

NEUROLOGICAL ANDCOGNITIVE EFFECTS OF HIVIN OLDER CHILDRENINFECTED WITH HIV

Currently, there exists a cohort ofadolescents who are long-term survivorsof vertical infection, often quite treat-ment-experienced. Adolescents whowere infected in infancy or young child-hood via blood or blood products are alsogenerally long-term survivors of variousantiretroviral treatments. Other adoles-cents and young adults are more recently

infected, generally via sexual transmissionin adolescence. A few of the long-termsurvivors of vertical infection have severestatic encephalopathies which first devel-oped in infancy, generally prior to anyantiretroviral treatment. Some experi-enced improvement in their neurologicalstatus when intensive antiretroviral treat-ment was begun, but are left with impor-tant cognitive and motor disabilities.When encephalopathy develops in late inthe course in long-term survivors, it issimilar to that seen in adults with AIDS.Encephalopathy occurring in patientswith viral acquisition during adolescenceis generally a part of severe, overt AIDS,and resembles adult AIDS encephalopa-thy. Cognitive problems predominate inmost patients, including attention andmemory difficulties.

DEVELOPMENT OF INFANTSOF HIV INFECTED MOTHERS

Zidovudine administered duringthe second half of pregnancy, intrave-nously during labor and delivery, and forsix weeks to the newborn infant reducestransmission by about two-thirds, fromabout 25% to 8% or less [Connor et al.,1994]. Since publication of the results ofACTG study 076 in 1994, pregnantwomen known to be HIV infected areencouraged to follow a similar treatmentprogram to prevent transmission of HIVto the infant. Treatment availability isgenerally limited to women in developedcountries. Serorevertors, the uninfectedchildren of HIV infected mothers, maybe exposed to other conditions in uterowhich are detrimental, despite escapinginfection with HIV. For example, amother with AIDS may transmit activeCMV or toxoplasmosis to her fetus, withsubstantial neurologic damage. Somenon-HIV infected infants are left withother causes of cognitive or physical dis-ability, including the effects of intrauter-ine recreational drug exposure, or com-plications of pregnancy. Nevertheless,when compared to infants from similarsocioeconomic backgrounds, the unin-fected infants of HIV infected mothersgenerally fare reasonably well [Mellins etal., 1994; Belman et al., 1996].

Infants who are HIV infectedwithout other manifestations of AIDShave been compared to uninfected (sero-revertor) exposed infants and to unex-posed infants. Even immediately afterbirth, there are reports of abnormalitiesof neurological state control in HIV in-fected infants compared to exposed, un-infected infants. Blasini et al. [1998] re-ported upon findings from a large cohortstudy of HIV exposed infants, the Wom-

212 MRDD RESEARCH REVIEWS ● HIV AND AIDS IN CHILDREN ● MITCHELL

en-Infant Transmission Study (WITS).They found that Brazelton scores tendedto indicate state control problems in in-fected infants.

In general, even without evidenceof AIDS, as a group, infected infantsscore lower than serorevertors on severalmeasures of early development, particu-larly language acquisition [Condini et al.,1991; Aylward et al., 1992; Gay et al.,1995]. Fine and gross motor functionmay be affected as well [Msellati et al.,1993; Parks and Danoff, 1999]. How-ever, others have reported comparablemental development of preschool-agedHIV infected children when comparedto socioeconomically and drug-exposurematched matched controls, althoughboth groups were subnormal [Fishkin etal., 2000]. Another study comparedHIV-infected infants to serorevertors,excluding children with symptomaticAIDS-defining diagnoses or lymphoidinterstitial pneumonia (LIP). Nozyce et alreported that the HIV infected childrenwere comparable to serorevertors whentested repeatedly over the first 24 monthsof life [Nozyce et al., 1994]. Similarly,Fishkin et al. found that although bothinfected and uninfected socioeconomi-cally matched pre-school aged subjectsscored below expectations on theWPPSI-R, there were not substantialdifferences between the groups [Fishkinet al., 2000].

Infants with vertically transmittedHIV and significant immunosuppressionmake up the major group presentingwith the early onset, progressive enceph-alopathy that accounts for most of thevery severe HIV-related neurodevelop-mental deficits. Untreated infants withhigh viral loads at birth or in the first fewmonths of life are at high risk. Encepha-lopathy may present insidiously, with ap-athy, poor head growth, initial hypotoniafollowed by hypertonia, or may presentwith an acute deterioration in neurode-velopmental status, rapidly losing previ-ously acquired landmarks. While otherAIDS-defining illnesses may be detectedsimultaneously with encephalopathy,progressive encephalopathy may be thesole AIDS defining illness in a significantpercentage of infants.

COGNITIVE FUNCTIONING OFOLDER CHILDREN WITH HIVINFECTION ACQUIRED VIABLOOD OR BLOOD PRODUCTS

Children with perinatal or latertransfusion-related infection who escapeearly onset encephalopathy generally areroughly comparable developmentally totheir peers, with only minor problems

noted on detailed psychometric testingprior to onset of AIDS, even as late as 8years after infection [Cohen et al., 1991].Encephalopathy is not a frequent AIDS-defining illness in this group. A numberof cohort studies of children acquiringHIV via blood products have found littledifference between infected children andtheir siblings or uninfected transfusedcomparison subjects. For example, theHemophilia Growth and DevelopmentStudy enrolled 333 boys and young menwith hemophilia in a comprehensive lon-gitudinal study of neurological and neu-rodevelopmental status, growth, and im-mune function. At baseline, prevalenceof neurological dysfunction was low, andgenerally limited to subjects already inadvanced stages of immunodeficiency,with CD41 cell counts below 200 [BaleJr. et al., 1993]. Similarly, abnormalitieson neuroimaging were limited to thesame group [Mitchell et al., 1993]. Sero-positive subjects did not differ on mostaspects of neuropsychological testingfrom seronegative subjects [Loveland etal., 1994]. Longitudinal followup of thegroup revealed that behavioral changesand diffuse muscle atrophy were the onlysignificant neurological findings attribut-able to HIV, and only very late in thecourse, usually in the six months preced-ing death [Mitchell et al., 1997]. Subtlechanges in attention were found prior tothe onset of more significant cognitivedysfunction, using a continuous perfor-mance task for assessment [Watkins et al.,2000]. However, the most powerful pre-dictor of death by the fifth year of fol-lowup was the presence of non-hemo-philia related diffuse muscle atrophy onneurological examination [Hoots et al.,1998].

A similar but smaller cohort ofboys with hemophilia, both infected withHIV and uninfected, were followed lon-gitudinally in North Carolina. Serialneuropsychological tests comparing sero-positive and seronegative subjects foundminimal differences, although bothgroups manifested similar mild deficits incognitive and motor functioning [Whittet al., 1993]. Hooper et al. [1997] alsoreported that there were no substantialdifferences between cognitive functionof HIV-infected and uninfected boyswith hemophilia.

NEUROLOGICALMANIFESTATIONS OFADVANCED AIDS

Symptoms similar to AIDS demen-tia complex as described in adults areoccasionally seen in adolescents with veryadvanced AIDS. Neurological manifesta-

tions include dementia, bradykinesia, andspasticity. Opportunistic CNS infectionssuch as toxoplasmosis and progressivemultifocal leukoencephalopathy (PML)are less common in children and adoles-cents than in adults, but are occasionallyseen. Primary CNS lymphoma is a rareneurological complication of pediatricAIDS, and may present with seizures orfocal neurological signs.

DIFFERENTIAL DIAGNOSISIn evaluating the developmental or

neurological problems of an infant orchild with HIV infection or exposure(serorevertors) other etiologic diagnosesmust be considered. The effects of intra-uterine recreational drug exposure, in-cluding substances such as cocaine, her-oin, amphetamines, marijuana, andalcohol must be considered, particularlywhen neurological signs and symptomsare present in the first days or weeks oflife. Infants with intrauterine cocaine ex-posure are often irritable, hypertonic, anddifficult to console [Chiriboga et al.,1995]. While on the average, cocaine-exposed infants have slightly smallerheads size than their peers, they do nothave the progressive microcephaly seenin HIV-related progressive encephalopa-thy [Chiriboga et al., 1999; Chiriboga,1998]. Opiates may cause acute with-drawal syndromes, with irritability, poorfeeding, and abnormal tone. Fortunately,there is little evidence of lasting neuro-logical damage from intrauterine drugexposure, other than from alcohol. Pro-gressive encephalopathies are not attrib-utable to intrauterine drug exposure.Other than in the child severely affectedwith fetal alcohol syndrome, overt men-tal retardation is not generally attributableto effects of intrauterine substances, inthe absence of secondary adverse effectsupon the pregnancy. School-age childrenwho were exposed to cocaine in uterohave IQ comparable to their unexposedpeers [Wasserman et al., 1998].

Other CNS congenital infectionssuch as toxoplasmosis and cytomegalovi-rus may affect the developing fetus of amother infected with HIV, even in theabsence of transmission of HIV. Therange of manifestations, as for all suchcongenital infections, is from asymptom-atic through devastating.

Other causes of static encephalop-athies such as cerebral malformations,cortical dysplasia, and hypoxic-ischemicencephalopathies may occur in childrenof HIV infected mothers, entirely inde-pendent of any effects of maternal HIVor its treatment. In infancy, the manifes-tations later to be diagnosed as “cerebral

213MRDD RESEARCH REVIEWS ● HIV AND AIDS IN CHILDREN ● MITCHELL

palsy,” such as early hypotonia progress-ing to hypertonia, hyperreflexia, and ab-normal primitive reflexes may not be dis-tinguishable from those of progressiveHIV encephalopathy.

Opportunistic infections of CNSare less commonly seen in children withAIDS than in adults, but may presentwith signs and symptoms which mimicthose of HIV encephalopathy, includingalterations in mental status, headaches,loss of motor function. Cerebral toxo-plasmosis is far less common in childrenthan adults, but presents as mass lesionswith seizures, focal neurological signs,headache and altered mental status.Cryptococcal meningitis has been re-ported in children with AIDS, as hasprogressive multifocal leukoencepalopa-thy (PML) [Berger et al., 1992]. In gen-eral, neuroimaging and CSF examinationwill distinguish these conditions fromprimary CNS effects of HIV.

NEUROIMAGINGCranial ultrasound in infected in-

fants may show early findings of vascu-lopathy, with echogenic stripes in thearea of the lenticulostriate vessels [Bodeand Rudin, 1995]. This is the area mostcommonly found to have calcifying mi-croangiopathy on CT scan, but the find-ings on CT may lag behind clinical evi-dence of encephalopathy. Progressivecalcifications, most commonly in thebasal ganglia, along with brain atrophyevidenced by enlarged ventricles and, toa lesser extent, enlarged cortical sulci arethe most common findings on CT scan[Belman et al., 1986; Brouwers et al.,1994]. The pattern of atrophy has beendescribed as “central atrophy” because ofthe predominant finding of elevation ofthe ventricular to brain ratio and the de-scription of “bicaudate atrophy” [Scar-mato et al., 1996].

Magnetic resonance imaging (MRI)may demonstrate both the atrophicchanges, as well as lesions in the whitematter [Mitchell et al., 1993]. Deep cal-cifications are sometimes less apparent onMRI than on CT scans, and more diffi-cult to appreciate [Johann-Liang et al.,1998]. The bright signal areas in the cen-trum semiovale on T2 weighted imagescorrespond to neuropathologic deepwhite matter changes. MRI is a bettertool than CT for delineation of mass le-sions, including those due to lymphomaand toxoplasmosis.

Functional brain imaging withPET scans has been reported to showdiffuse hypometabolism in a small num-ber of children with severe encephalop-athy, and more limited hypometabolic

areas in infected children without overtencephalopathy [Depas et al., 1995].

Late in the course of AIDS en-cephalopathy, vascular disease may man-ifest as cerebral artery aneurysms [Hussonet al., 1992], which may expand greatlyand/or progress to rupture. Medium andlarge vessel disease may also manifest asischemic stroke [Philippet et al., 1994].

CONGENITAL CMV ASCOFACTOR IN AIDSENCEPHALOPATHY

A number of investigators have ob-served the apparent association of coin-fection with cytomegalovirus (CMV)and HIV disease progression. CongenitalCMV is not found more frequently inHIV infected than in HIV-exposed in-fants of HIV infected mothers, but ismore often acquired in the first fewmonths of life. Kovacs et al. [1999] notonly found that infants coinfected withHIV and CMV had a higher rate of pro-gression to symptomatic stages of AIDS,but also that encephalopathy was sub-stantially more frequent in coinfected in-fants (35% versus 9% by 18 months ofage).

TREATMENT EFFECTSEarly evidence suggested that ag-

gressive treatment reverses encephalopa-thy. Continuous intravenous infusions ofzidovudine in children with encephalop-athy improved cognitive functioning af-ter 6 months, with a median improve-ment of 15 points in developmentalquotient or IQ, which generally wasmaintained for at least 12 months [Brou-wers et al., 1990]. Neuroimaging docu-mented improvement in baseline brainatrophy as assessed by ventricular to brainvolume ratios after 6 months of treatment[DeCarli et al., 1991]. These findingswere in treatment-experienced children,and were obtained with zidovudinemonotherapy.

Increasing evidence suggests thataggressive antiretroviral treatment mayhalt or even reverse signs of encephalop-athy, even in the face of apparently staticstructural damage such as basal gangliacalcifications and deep white matter ab-normalities. Some early, postive reportssuggest that AIDS dementia symptomsmay be partially reversible in adultstreated with highly active antiretroviraltreatment (HAART), combining at leastone protease inhibitor with at least twoother antiretroviral agents. There are sev-eral reports of impressive improvementin neurological function in children withrecent onset of encephalopathy started onHAART [Tepper et al., 1998]. How-

ever, others dispute the reversibility ofneurologic symptoms with anythingother than continuous intravenous infu-sion of zidovudine [Guigonis et al.,1998].

TREATMENT DIRECTED ATENCEPHALOPATHY,INDEPENDENT OF VIRALSUPPRESSION

There are some indications thatcalcium channels and NMDA receptorsare involved in mediating the neuronaldamage caused by HIV-1 [Lipton, 1994].Several trials of calcium channel blockersin adults with AIDS dementia, however,have not shown positive results. To date,no neuroprotective or neurosalvage mea-sures have been subjected to randomizedclinical trials in children with HIV en-cephalopathy.

ADVERSE EFFECTS OFTREATMENT

Nucleoside reverse transcriptaseinhibitors (NRTIs) such as zidovudinemay cause a severe, even fatal, lactic ac-idosis. This is due to depletion of mito-chondrial DNA, causing multisystemdysfunction including encephalopathy,peripheral neuropathy, and myopathy.Church et al recently reported a youngchild whose progressive encephalopathywas initially attributed to HIV encepha-lopathy, despite good control of othermanifestations of disease and undetect-able viral load [Church et al., 2001]. AnMRI showed patchy lesions in the deepwhite matter, hyperintense on T2 se-quences, which were considered to betypical of HIV encephalopathy. His ther-apy was switched from a combinationcontaining oral zidovudine to continuousintravenous infusion of zidovudine. Hedeveloped severe multisystem failure in-cluding profound lactic acidosis, neurop-athy, enteropathy, hepatic dysfunction,myopathy. All of the findings eventuallyreversed with intensive intervention, in-cluding elimination of NRTIs from histreatment. Similar cases have been de-scribed in adults, many with fatal out-come.

There has recently been concernraised that intrauterine exposure to NR-TIs may cause mitochondrial damagewhich is not reversed after stopping themedication at the typical age of 6 weeksin uninfected infants. Two uninfected in-fants of HIV infected mothers in Francedeveloped progressive, fatal encephalop-athies, one characterized as Leigh syn-drome, the other as Alper syndrome[Blanche et al., 1999; 2000]. Both wereexposed in utero to zidovudine and lami-

214 MRDD RESEARCH REVIEWS ● HIV AND AIDS IN CHILDREN ● MITCHELL

vudine, were uninfected with HIV (se-rorevertors), and had no other identifiedgenetic risk factors for mitochondrial cy-topathies. Six other children were retro-spectively identified in France who de-veloped either biochemical, clinical orboth manifestations of mitochondrialdysfunction after exposure to these twoNRTI medications in utero and for thefirst six weeks of life. These reports raisedgreat concern regarding the possibility ofpermanent mitochondrial toxicity fromantiretroviral treatment to reduce mater-nal transmission of HIV. A U.S. basedgroup subsequently surveyed all reporteddeaths of children born to HIV infectedmothers from five large prospective co-horts. No cases suspicious of mitochon-drial cytopathy were found, and therewas no increase in deaths among antiret-roviral exposed uninfected children com-pared to those with no antiretroviraltreatment of either mother or child [Peri-natal Safety Review Working Group,2000]. A detailed review of a large num-ber of zidovudine exposed, uninfectedchildren followed via Pediatric AIDSClinical Trials Group (PACTG) study219 failed to find any adverse fetal ordevelopmental effects of in utero expo-sure to zidovudine [Culanane et al.,1999]. f

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