HIV AIDS and the Nervous System: Handbook of Clinical Neurology

361 Pages·2007·11.64 MB·English

by  Peter Portegies

Foreword
WeareproudatthepublicationofthisseventhvolumeinthethirdseriesoftheHandbookofClinicalNeurology.
TheHandbookwasoriginallyconceivedbyPierreVinkenandGeorgeBruyn,andthefirstvolumewaspublished
in1968.Thisnew—third—seriesstartedin2004andcoversadvancesintraditionalareasofclinicalneurology
andtheneurosciencesinsubjectsembracedbyearliervolumes,aswellasnewcontemporarytopicsthatwerenot
previously considered. The neurobiological aspects of the nervous system in health and disease are included in
order to clarify physiological and pathogenic mechanisms and to provide new therapeutic strategies for neurolo-
gical disorders. Data related to epidemiology, imaging, genetics, and therapy are also emphasized in the new
series.
Thepresentvolume,editedbyPeterPortegiesandJosephR.Berger,isthefirstHandbookvolumededicatedto
HIVinfectionandneuro-AIDSandhasallthecharacteristicswewantedintheseries.AIDSwasfirstdescribedin
1981 and was soon found to be accompanied by serious complications, such as opportunistic infections, central
nervous system tumors, spinal cord disorders, peripheral neuropathies, myopathies, and a progressive encepha-
lopathy. In response to advances in molecular biology and the advent of other investigative techniques, under-
standing of the basic mechanisms of the disease and the development of therapeutic strategies for the disorder
grew very rapidly, and now, almost 25 years later, the outlook for HIV-infected patients has totally changed in
Western countries: patients on antiretroviral therapy may have prolonged survival with few or no complications.
However,duetofinancialandpoliticalconstraints,AIDSisstilladeadlydiseaseinotherpartsoftheworld,such
as Africa.
Portegies and Berger are to be congratulated on bringing together such an excellent group of experts in this
truly multidisciplinary volume, which includes chapters on neuroepidemiology, third-world characteristics of
thedisease,neuropharmacology,clinicalneurology,neuropsychology,neuroradiology,neuropathology,neurophy-
siology, neurovirology, neuropathogenesis, and animal models of HIV-related neurological diseases. As series
editors we are also very grateful to the authors of the chapters and to the editorial staff of Elsevier BV, and
particularly to Lynn Watt and Michael Parkinson in Edinburgh, who have all provided invaluable assistance.
Michael J. Aminoff
Franc¸ois Boller
Dick F. Swaab
List of contributors
R. J. Baumann S. Dawes
Department of Neurology, University of Kentucky, HIV Neurobehavioral Research Center, University of
Lexington, KY, USA California, San Diego, CA, USA
J. R. Berger A. Di Rocco
Department of Neurology, University of Kentucky, New York University School of Medicine, New York,
Lexington, KY, USA NY, USA
G. L. Birbeck P. S. Espinosa
Departments of Neurology, Epidemiology & African Department of Neurology, University of Kentucky,
Studies, Michigan State University, East Lansing, MI, Lexington, KY, USA
USA and Chikankata Health Services, Mazabuka,
Zambia L. B. Estanislao
The Mount Sinai Medical Center, New York, NY,
B. J. Brew USA
Department of Neurology, St Vincent’s Hospital,
University of New South Wales, Sydney, Australia B. B. Gelman
Texas NeuroAIDS Research Center, University of
M. C. Brouwer Texas Medical Branch, Galveston, TX, USA
Department of Neurology, Academic Medical Center,
University of Amsterdam, The Netherlands H. E. Gendelman
The Center for Neurovirology and Neurodegenerative
J. L. Buescher Disorders, Department of Pharmacology, Nebraska
The Center for Neurovirology and Neurodegenerative Medical Center, Omaha, NE, USA
Disorders, Department of Pharmacology, Nebraska
Medical Center, Omaha, NE, USA M. Gisslen
Department of Infectious Diseases, Go¨teborg
A. T-A. Chan University, Sahlgrenska University Hospital,
The Mount Sinai Medical Center, New York, NY, Go¨teborg, Sweden
USA
C. A. Given II
L. M. Chirch Department of Radiology, University of Kentucky
Stony Brook University School of Medicine, Stony Chandler Medical Center, Lexington, KY, USA
Brook, NY, USA
I. Grant
P. Cinque HIV Neurobehavioral Research Center, University of
Clinic of Infectious Diseases, San Raffaele Scientific California, San Diego, CA, USA
Institute, Milan, Italy
S. Gross
B. A. Cohen The Center for Neurovirology and Neurodegenerative
Feinberg School of Medicine, Northwestern Disorders, Department of Pharmacology, Nebraska
University, Chicago, IL, USA Medical Center, Omaha, NE, USA
x LIST OF CONTRIBUTORS
L. Hagberg E. O. Major
Department of Infectious Diseases, Go¨teborg Laboratory of Molecular Medicine and Neuroscience,
University, Sahlgrenska University Hospital, NINDS, NIH, Bethesda, MD, USA
Go¨teborg, Sweden
P. Portegies
S. A. Houff Department of Neurology, OLVG Hospital,
Department of Neurology, University of Kentucky, Amsterdam, The Netherlands
Lexington, KY, USA
W. G. Powderly
T. Ikezu UniversityCollege Dublin, Mater University Hospital,
The Center for Neurovirology and Dublin, Ireland
Neurodegenerative Disorders, Department of
Pharmacology, Nebraska Medical Center, Omaha, R. W. Price
NE, USA Department of Neurology, University of California,
San Francisco General Hospital, San Francisco,
A. Jackson CA, USA
University College Dublin, Mater UniversityHospital,
Dublin, Ireland E. Richard
DepartmentofNeurology,AcademicMedicalCenter,
C. Kirton UniversityofAmsterdam,Amsterdam,TheNetherlands
The Mount Sinai Medical Center, New York, NY,
USA D. M. Simpson
TheMountSinaiMedicalCenter,NewYork,NY,USA
B. J. Luft
Stony Brook University School of Medicine, Stony S. Verma
Brook, NY, USA TheMountSinaiMedicalCenter,NewYork,NY,USA
Contents
Foreword vii
List of contributors ix
1. Introduction to HIV infection and neuro-AIDS 1
Peter Portegies and Joseph R. Berger (Amsterdam, The Netherlands and Lexington, KY, USA)
2. Neuroepidemiology of HIV/AIDS 3
Robert J. Baumann and Patricio S. Espinosa (Lexington, KY, USA)
3. HIV neurology in the developing world 33
Gretchen L. Birbeck (East Lansing, MI, USA and Mazabuka, Zambia)
4. The neuropathogenesis of HIV-1 infection 45
James L. Buescher, Sara Gross, Howard E. Gendelman and Tsuneya Ikezu (Omaha, NE, USA)
5. Neurological sequelae of primary HIV infection 69
Bruce J. Brew (Sydney, Australia)
6. AIDS dementia complex 79
Bruce J. Brew (Sydney, Australia)
7. Neurocognitive assessment of persons with HIV disease 93
Sharron Dawes and Igor Grant (San Diego, CA, USA)
8. HIV myelopathy 123
Alessandro Di Rocco (New York, NY, USA)
9. Peripheral neuropathy in HIV infection 129
Susama Verma and David M. Simpson (New York, NY, USA)
10. Myopathy in HIV infection 139
Adrian Tien-Auh Chan, Carl Kirton, Lydia Estanislao and David M. Simpson (New York, NY, USA)
11. Cerebral toxoplasmosis in AIDS 147
Lisa M. Chirch and Benjamin J. Luft (Stony Brook, NY, USA)
12. Cryptococcal infection 159
Arthur Jackson and William G. Powderly (Dublin, Ireland)
13. Progressive multifocal leukoencephalopathy 169
Joseph R. Berger (Lexington, KY, USA)
xii CONTENTS
14. Other opportunistic infections of the central nervous system in AIDS 185
Bruce A. Cohen and Joseph R. Berger (Chicago, IL and Lexington, KY, USA)
15. Primary central nervous system lymphoma 221
Edo Richard, Matthijs C. Brouwer and Peter Portegies (Amsterdam, The Netherlands)
16. Neuroimaging of the HIV/AIDS patient 229
Curtis A. Given II (Lexington, KY, USA)
17. Cerebrospinal fluid markers in central nervous system HIV infection and
AIDS dementia complex 261
Paola Cinque, Bruce J. Brew, Magnus Gisslen, Lars Hagberg and
Richard W. Price (Milan, Italy; Sydney, Australia; Go¨teborg,
Sweden; San Francisco, CA, USA)
18. The neuropathology of HIV 301
Benjamin B. Gelman (Galveston, TX, USA)
19. Neuropharmacology of HIV/AIDS 319
Sidney A. Houff and Eugene O. Major (Lexington, KY and Bethesda, MD, USA)
Subject index 365
Color plate section 369
HandbookofClinicalNeurology,Vol.85(3rdseries)
HIV/AIDSandtheNervousSystem
P.Portegies,J.R.Berger,Editors
#2007ElsevierB.V.Allrightsreserved
Chapter 1
Introduction to HIV infection and neuro-AIDS
PETER PORTEGIES* ANDJOSEPHR.BERGER
OLVGHospital,Amsterdam, TheNetherlandsandUniversityofKentucky,College ofMedicine,Lexington,KY,USA
The acquired immune deficiency syndrome (AIDS), asintheearly1980s.However,forclinicalneurologists
causedbyinfectionwiththeretrovirusknownashuman the HIV-infected patient with neurological disease is
immunodeficiency virus (HIV), was first described in a diagnostic and therapeutic enigma. The challenges
1981. Not long afterwards, reports began to appear of arise because these patients often present in an atypi-
neurologicalcomplications,includinganunusualence- cal fashion, exhibit unpredictable reactions to HAART
phalopathy, in affected patients. In the ensuing years, and specific therapies, and often have more than one
the nature and spectrum of the neurological complica- neurological complication developing simultaneously.
tions occurring in these immunosuppressed patients Furthermore, the neurological disease may be entirely
became better defined. These disorders included opp- unrelated to the underlying HIV infection. Therefore,
ortunistic infections rarely seen in immunologically theproblemsinthesepatientsremaincomplexandneed
healthyindividuals,CNStumors,spinalcorddisorders, neurologists with knowledge of and expertise in HIV
peripheral neuropathies, myopathies and a progressive infection.
encephalopathy. Some of the opportunistic infections
could be treated well; others had a very poor prog- 1.1. The epidemic in 2006
nosis, partly due to the fact that the underlying immu-
nodeficiency could not be treated. The face of AIDS The global infection is not under control. The global
changed when antiretroviral drugs were developed. burdenofthediseaseremainsenormous.Morethan40
Zidovudine was introduced in 1986, and combination millionpeopleworldwideareinfectedtoday.Stillthere
therapy of two or three drugs became available in the arealmost5millionnewinfectionseachyearandin2005
early 1990s. In patients on highly active antiretroviral the estimated death toll was 3.1 million people [AIDS
therapy(HAART)morbidityandmortalitydroppeddra- Epidemic Update: December 2005, available online
matically. The incidence of many of the opportunistic at http://data.unaids.org/pub/EpiReport/2006/2006_
infections, including the neurological infections, EpiUpdate_en.pdf]. Only a small fraction of patients
decreased.Forsomeoftheneurologicalcomplications hasaccesstoantiretroviraltreatment.Despitetheefforts
that were thought to be more directly related to HIV of many (non-governmental organizations, state gov-
itself, HAART was beneficial (dementia); for others, ernments,WHO,UNAIDS),thehurdleswefaceinpro-
suchasAIDS-relatedperipheralneuropathyandmyelo- viding adequate care to those infected continue to be
pathy,theinfluenceoftreatmentwaslimited,atbest. extraordinarily challenging. This is particularly true
Almost25yearslaterHIVinfectionhasevolvedinto in areas of the world where the pandemic has been
a different disease. Patients on HAART live normal especiallydevastating,suchassub-SaharanAfrica.Epi-
lives,and havelittleornocomplicationsoftheirinfec- demiological studies regarding the burden of AIDS-
tion. Untreated patients are still at risk for developing relatedneurologicaldiseasefromlargepartsoftheworld
a severe immunodeficiency with all the well-known are hardly available and neurological care, in general,
complications, including the neurological ones. The andneuro-AIDSexpertise,specifically,isverylimited
approach to these neurological complications did not in many countries where HIV infection has reached
change;thetreatmentformanyofthemisstillthesame epidemic proportions. An up-to-date report of the
*Correspondence to: Peter Portegies, MD, PhD, Department of Neurology, OLVG Hospital, PO Box 95500, 1090 HM
Amsterdam, The Netherlands. E-mail: [email protected], Tel: þ 31-20-599-3044, Fax: þ 31-20-599-3845.
2 P. PORTEGIES AND J. R. BERGER
epidemiology of HIV infection focused on the neuro- impact of HAART on the various neurological compli-
logical complications of AIDS and the situation in cations of AIDS is widely discussed in the following
underdeveloped and developing countries is discussed chapters.
in depth in this book.
1.3. What have we learned from HIV and its
1.2. Neuro-AIDS in 1985 and 2005 interaction with the nervous system?
SincethebeginningoftheHIVepidemicapproximately Ourunderstandingofthenatureandpathogenesisofthe
10% of patients have presented with a neurological neurologicalcomplicationsofHIV,and,forthatmatter,
complication as the first manifestation of their HIV of viral illness of the nervous system, has increased
infection, 40–60% develop neurological disease in the dramaticallyinthe past 25years.We know thatneuro-
course of their disease and most patients (80%) have logical disease in HIV-infected persons is common,
neuropathologicalabnormalitiesatautopsy.Assimilar thoughincreasinglylesssointhefaceoftreatmentwith
studieshavenotbeenperformedintherecentpast,par- HAART.Theseillnessesareacauseofsignificantmor-
ticularlysincetheintroductionofHAART,itisunclear bidityandmortality.Nopartoftheneuraxisisinvulner-
whether these percentages still pertain. Clearly, in able to the HIV-related disease; the brain, spinal cord,
regions of the world where people have access to peripheral nerves and muscles may all be affected.
HAART,theincidenceofmanyofthecommonneuro- Many of the neurological diseases that have been
logical complications of AIDS has decreased. For described since the recognition of AIDS are unique.
instance, as with the non-neurological opportunistic Often, the clinical picture is confusing; patients may
infections,theCNSinfectionsofcerebraltoxoplasmosis present with two or more neurological disorders that
and cryptococcal meningitis have become rare in have developed simultaneously and expected findings,
patientswithnormalCD4-cellcounts.HAARTmayalso such as headache and neck stiffness with cryptococcal
preventthedevelopmentofprimarycentralnervoussys- meningitisorfocaldeficitswithlargeCNSmasslesions
tem lymphoma (PCNSL) and progressive multifocal from toxoplasmosis or PCNSL, are absent. Therefore,
leukoencephalopathy (PML) in those individuals we have approached these patients with greater diag-
responding to the medications. Similarly, the classic nostic aggressiveness and are more inclined to perform
picture of HIV-dementia has declined dramatically, neuroimaging studies and cerebrospinal fluid analysis
although cognitive abnormalities still develop even in than we might otherwise have done. We have also
thefaceofnormalimmunefunction.Likewise,despite increasingly used new techniques, like polymerase
HAART, peripheral neuropathy is still a frequent chain reaction, in establishing diagnoses. We have also
complication. learnedthattheCNSmayserveasareservoirforHIV;
The treatment of patients who present with a neuro- one that may be relatively protected from otherwise
logicaldiseaseisnotuncomplicated.Specifictreatment effective antiretroviral therapy and one from which the
is available for some, particularly opportunistic infec- virus may reseed the body.
tions,suchastoxoplasmosisandcryptococcalmeningi- We have learnt a great deal of the interaction of
tis; however, for other conditions there is no treatment HIV and the nervous system and of the pathogenesis
of demonstrated value, such as PML. The recovery of of CNS viral infection, in general, such as the role of
immunological impairment that attends the initiation microglia cells, cytokines and chemokines in the
of HAART is generally beneficial, but sometimes the defenseanddamageoftheCNSinviralinfectionhave
immune reconstitution inflammatory syndrome (IRIS) been studied extensively.
develops resulting in temporary worsening of the Thisvolumeprovidesanin-depthoverviewoftheneu-
patient’s condition or, in some instances, contributing rology ofHIVinfectionasat2006. Wehaveattempted
to their death. When no specific treatment is available, tomakethisvolumeascomprehensiveaspossiblewith
HAARTwithitsassociatedimmunerecoveryisenough all aspects of neurology of AIDS covered. Among the
tostabilizeorreverseaneurologicaldisorderasmaybe chapters are those dealing with clinical neurology,
seen in some patients with AIDS-related PML. An neuroradiology, neuropathology, cerebrospinal fluid,
explanation for the success of such treatment in some neurophysiology,neurovirology,neuropathogenesisand
patients and the failure in others remains unclear. The animalmodelsofHIV-relatedneurologicaldisease.
HandbookofClinicalNeurology,Vol.85(3rdseries)
HIV/AIDSandtheNervousSystem
P.Portegies,J.R.Berger,Editors
#2007ElsevierB.V.Allrightsreserved
Chapter 2
Neuroepidemiology of HIV/AIDS
ROBERT J. BAUMANN * AND PATRICIO S. ESPINOSA
Department of Neurology, University of Kentucky, Lexington, KY, USA
2.1. Introduction prevent disease (UNAIDS, 2004). Two viral types have
been described in humans, HIV-1 and HIV-2, both of
Human immu nodef iciency vir us (HIV) infect ion and which originated in Africa. HIV-1 has now become dis-
acquire d immunodef icienc y syndr ome (AID S) have persed around the world while HIV-2 is primarily con-
developed as one of our mos t important public heal th centrated in Africa. HIV-1 virus has 3 subgroups: M, O
problem s. Curre nt estimat es are that 38 mi llion people and N; the M subgroup has several subtypes: A, B, C,
are living with HIV wor ldwide. In 2003 annual mor tal- D, E, F, G, H, J and K. One epidemiological feature
ity was estimat ed at 2.9 million with over 20 million o f th es e s ub ty pe s i s t ha t d ua l i nf ec ti on h a s b ee n r ep or te d
deaths havi ng occurred since the first case s of AIDS between types and subtypes; however, clinically, they are
were iden tified in 19 81 (UNA IDS, 2004 ). Al so in impossible to differentiate.
2003, an est imated 4.8 mi llion peopl e became new ly
infect ed with HIV (UNA IDS, 2004 ). According to the 2.1.3. Case defin ition
Cente rs for Disease Control and Preve ntion (CDC) , in
2003 an estimat ed 1,03 9,000 to 1,185,000 pers ons in The case defi nition for HIV inf ection, updat ed in
the USA were living with HIV/A IDS. The CDC esti- December 1999 by the CDC, applies to both HIV- 1
mates that appro ximatel y 40,000 persons become and HIV-2 infections (Table 2.1) (CDC, 1999). It is the
infect ed with HIV each year (CDC , 2005 ). basis of the USA HIV case surveillance effort to categor-
ize, track and control this disease, though elsewhere in the
2.1.1. The origin of HIV worldcasedefinitionscanvary.
It is believed that HIV was present in rural Africa 2.1.4. Mode and trend of transmi ssion of HIV
for decades befor e the USA outbr eak in the 1980s.
Serum from residents o f rural Zair e obtaine d in the HIV can be transmitted by sexual contact, parenteral
1970s provi des evid ence of the existe nce of this infec- inoculation and perinatally from mother to child. Other
tion before its iden tificatio n as a specific d isorder categories of transmission such as insect bites, saliva,
( Nemeth et al., 1986; Nzil ambi et al., 1988 ). In June tears and casual contact (hand shake, sharing clothes,
1981 the CDC reported five homosexua l men in Los etc.) have not been proven (Li fs on , 1 98 8).
Angeles, California, who developed Pneumocystis cari- Primary transmission is by sexual contact with epi-
nii and later in the same month 20 homosexual men in demiological evidence suggesting anal intercourse as
New York were diagnosed with Kaposi sarcoma, mark- the most efficient mode of transmission (Biggar &
ing the beginning of the world epidemic (CDC, 1981). Rosenberg, 1993; Folch et al., 2005). Since the onset
of the epidemic the group with highest risk of HIV
2.1.2. Gene tic diversi ty of HIV i n f e ct io n h av e b ee n m en w h o h av e s ex w it h m e n
(CDC,1981,2003).Surveillancereportsshowthatmost
HIV, a retroviru s, inf ects humans causi ng impairm ent reported cases of HIV infection in the USA occur
of the ability of the immu ne system to battle and among men who have sex with men, followed by het-
*Correspondence to: Robert J. Baumann, MD, Professor of Neurology and Pediatrics, Director, Child Neurology Program,
Department of Neurology, University of Kentucky, Kentucky Clinic L 409, Speed Sort 0284, Lexington, KY 40536-0284,
USA. E-mail: [email protected], Tel: þ1-859-323-6702. Ext 242.
4 R. J. BAUMANN AND P. S. ESPINOSA
Table2.1
CasedefinitionforHIVinfection
I.Inadults,adolescents,orchildrenagedgreaterthanorequalto18months,aareportablecaseofHIVinfectionmust
meet atleastoneofthefollowingcriteria:
LaboratoryCriteria:
a)PositiveresultonascreeningtestforHIV antibody(e.g.,repeatedly reactiveenzymeimmunoassay),followedby
apositiveresultonaconfirmatory(sensitiveandmore specific)testforHIV antibody(e.g.,Westernblotor
immunofluorescenceantibodytest)
b)Positiveresultorreportofadetectable quantityonanyofthefollowingHIV virologic(non-antibody)tests:
-HIV nucleicacid (DNAorRNA)detection(e.g., DNApolymerase chainreaction[PCR]orplasmaHIV-1RNA)b
-HIV p24antigentest,includingneutralization assay
-HIV isolation(viralculture)
ClinicalorOtherCriteria(iftheabovelaboratorycriteria arenotmet)
a) DiagnosisofHIVinfection,basedonthelaboratorycriteriaabove,thatisdocumentedinamedicalrecordbyaphysician.
b)Conditionsthat meetcriteria includedinthecase definitionforAIDS
II.Inachildagedless than18months,a reportablecaseofHIVinfectionmustmeetatleast oneofthefollowing
criteria:
LaboratoryCriteria:
Definitive:
a)Positiveresultsontwoseparatespecimens(excludingcordblood)usingoneormoreofthefollowingHIVvirologic(non-
antibody)tests:
-HIV nucleicacid (DNAorRNA)detection
-HIV p24antigentest,includingneutralization assay,inachildgreater thanorequal to1monthofage
-HIV isolation(viralculture)
Presumptive:Achildwhodoesnotmeetthecriteria fordefinitiveHIVinfection butwhohas:
b)Positiveresultsononlyonespecimen(excludingcordblood)usingtheaboveHIV virologictestsandnosubsequent
negativeHIVvirologic ornegativeHIV antibodytests.
ClinicalorOtherCriteria(iftheabovelaboratorycriteria arenotmet)
a) DiagnosisofHIVinfection,basedonthelaboratorycriteriaabove,thatisdocumentedinamedicalrecordbyaphysician.
b)Conditionsthat meetcriteria includedinthe1987pediatricsurveillancecase definitionforAIDS
III.Achildagedlessthan18monthsborntoanHIV-infectedmotherwillbecategorizedforsurveillancepurposesas
“notinfectedwithHIV” ifthechilddoesnotmeet thecriteriaforHIVinfectionbutmeets thefollowingcriteria:
LaboratoryCriteria:
Definitive:
a)AtleasttwonegativeHIVantibody testsfromseparatespecimens obtainedatgreaterthanorequalto6monthsofage
or
b)AtleasttwonegativeHIVvirologictestscfromseparatespecimens,bothofwhichwereperformedatgreaterthanorequal
to1 monthofageandoneofwhichwasperformedatgreater thanorequal to4monthsofage
AND
c)NootherlaboratoryorclinicalevidenceofHIVinfection(i.e.,hasnothadanypositivevirologictests,ifperformed,and
hasnothadanAIDS-definingcondition)
Presumptive:Achildwhodoesnotmeettheabovecriteria fordefinitive“notinfected”statusbutwhohas:
a)OnenegativeEIAHIVantibodytestperformedatgreaterthanorequalto6monthsofageandNOpositiveHIVvirologic
tests, ifperformed
or
b)OnenegativeHIVvirologictestcperformedatgreaterthanorequalto4monthsofageandNOpositiveHIVvirologic
tests, ifperformed
or
c)OnepositiveHIVvirologictestwithatleasttwosubsequentnegativevirologictests,datleastoneofwhichisatgreater
thanorequalto4monthsofage;ornegativeHIVantibodytestresults,atleastoneofwhichisatgreaterthanorequalto
6monthsofage
AND
d)NootherlaboratoryorclinicalevidenceofHIVinfection(i.e.,hasnothadanypositivevirologictests,ifperformed,and
hasnothadanAIDS-definingcondition).