Clin Pathol 1992;45:850-854

Clinical and immunological assessment of HIVinfection

A G Bird

IntroductionHuman immunodeficiency virus (HIV) infec-tion results in a progressive immunodeficiencyprimarily affecting T cell mediated immunity.It is also associated with direct damage to otherorgans including the brain and gastrointestinaltract which may be the direct result of eitherprimary viral pathogenicity or a consequence

ofimmunopathological effects. This review willcover only aspects of the clinical presentationof HIV- infection resulting from the associatedimmunodeficiency and its laboratory assess-

ment.Accurate clinical staging is essential for

epidemiological monitoring of the HIV epi-demic, overall, in patient selection for clinicaltrials, and is of increasing importance in theassessment of individual patients for thera-peutic intervention. Laboratory monitoring isgaining increasing importance in the initialstaging of disease in individual patients, in theidentification of immunological progression ofthose patients who remain asymptomatic, andin the recruitment to and assessment of clinicaltrials of new therapeutic agents against HIVinfection.

HIV ImmunologyUnit, Department ofMedicine, RoyalInfirmary, EdinburghEH3 9YWA G BirdCorrespondence to:Dr A G BirdAccepted for publication13 January 1992

Staging of HIV diseaseIn most individuals infected with HIV evi-dence of cellular immune deficiency appearsafter a latent period of good health that usuallyextends for a number of years after primaryviral infection. Available evidence from severalcohort studies suggests that 10 years afterinfection half of adults acquiring infection byany of the recognised routes will have devel-oped AIDS and that most of the remainder willhave either symptomatic disease which doesnot yet fulfill the case definition for AIDS or

laboratory evidence of persistent virus infec-tion and subclinical immune deficiency.'However, in all studies of such duration thereremains a residue of individuals with littleclinical or laboratory evidence of cellularimmunodeficiency. Whether this minority pop-ulation identifies a group of individuals whowill only show late evidence of progression or

who genuinely represent individuals who are

immune to the pathogenic potential of HIVwill only become apparent with longer termfollow up.

Clinical presentation and natural history ofdisease is less predictable and more diverse inchildren who have acquired the infection verti-cally during gestation or at childbirth, and isbeyond the scope of this article. Readers are

referred to review articles dealing specifically

with paediatric aspects of HIV infection.5 7Because viral infection in adults, and the

associated immunodeficiency, is progressive inmost individuals, several clinical staging sys-tems have been proposed which are essentiallyhierarchical and describe events which onceoccurred do not revert to earlier stages. How-ever, with the increasing use of specific treat-ment in patients it is now possible in practice toreturn patients temporarily to earlier levels ofsuch classifications. Such reversion is seenparticularly in laboratory markers of immuno-logical progression in patients receiving anti-retroviral treatment.The most widely adopted Centers for Dis-

ease Control (CDC) clinical staging system ofHIV infection is reproduced in table 1 but maysoon be replaced by a proposed CDC/WHOclassification which will incorporate both labo-ratory and clinical markers (table 2). Theproposed new classification recognises theimportance of the long asymptomatic stage ofdisease in determining the eventual outcome of

Table I Centers for Disease Control (CDC) classificationofHIV infection

Stage I Acute HIV infection and seroconversionStage II Asymptomatic HIV infectionStage III Persistent generalised lymphadenopathyStage IV A Constitutional disease (old AIDS related

complex (ARC))B Neurological diseaseC Severe clinical immunodeficiency

Cl CDC AIDS definitionC2 severe infections outwith AIDSdefinition

D Secondary cancers within AIDS definition:Kaposi's sarcomaNon-Hodgkin's lymphoma

E Other conditions

Table 2 Proposed CDCIWHO classification system

I Clinical:Category A -Primary clinical HIV infection

(seroconversion illness)-Asymptomatic HIV infection-Persistent generalised lymphadenopathy

Category B -Conditions indicative of HIV associatedcellular immune deficiency not listed inCategory C, such as,-Bacterial pneumonia or meningitis-Pharyngeal or vaginal candidiasis-Cervical dysplasia or carcinoma-Oral hairy leucoplakia-Recurrent or multidermatomal herpes

zoster-Pulmonary tuberculosis-Idiopathic thrombocytopenic purpura-Unexplained constitutional disturbance

Category C -Old CDC stages IV B, C1, C2, D, EII Laborawry:

CD4 cells x 109/l Total lymphocyte count x 10911(1) > 0-5 > 2(2) 0-2-09 1-1 9(3) <0-2 < 1

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Clinical and immunological assessment of HIV infection

the disease process and the need to directtherapeutic trial intervention at this group ofpatients. It includes clinical and laboratorystaging systems assessed in parallel to improvediscrimination of disease stages and recognisesthe importance of laboratory markers of dis-ease in the subclassification of asymptomaticpatients. The addition of lymphocyte counts inthis classification identifies the reality that inmany countries reliable methodologies foraccurate quantitation ofCD4 counts, althoughdesirable, are not routinely available.

Acute (primary) HIV infectionAcute HIV infection is identified as a clinicalevent in only about 15-20% of individuals.Defined as an acute viral illness resemblinginfections mononucleosis and less commonlyassociated with acute neurological manifesta-tions, which include aseptic meningoencepha-litis or neuropathy, these symptoms aretemporally associated with the first appearanceof HIV antibodies in infected individuals.8Thisacute viral illness is self limiting in virtually allcases but if prolonged has been associated withmore rapid subsequent progression to sympto-matic immunodeficiency.9

Asymptomatic HIV disease andpersistent generalised lymphadenopathyThe proposed new category A of the CDC/WHO staging system combines primary viralinfection together with asymptomatic diseaseand persistent generalised lymphadenopathy(PGL) as a single staging entity. This summa-tion is a recognition of the fact that naturalhistory studies have indicated that asympto-matic HIV seropositive (PGL) subjects ofknown seroconversion date have no increasedpropensity to disease progression when com-pared with similar subjects without clinicallymphadenopathy.1' Most HIV seropositveindividuals remain in category A for longperiods of time and yet within this stage a widerange of immunological changes of differentseverity can be seen. It is in this category thatthe inclusion of immunological staging willadd most additional information.

Early manifestations of HIV associatedimmunodeficiencySymptomatic HIV immunodeficiency gener-ally appears many years after initial viralinfection. Most, but not all, patients passthrough a sequence of mild and progressiveconstitutional disturbance frequently asso-ciated with minor opportunistic infectionsidentified in category B. Few of these condi-tions are restricted to HIV infection and somecan be frequently encountered in non-HIVinfected individuals who are well or mildlyimmunocompromised. Oral hairy leucoplakiaor recurrent or extensive herpes zoster aremost typical of the earlier stage HIV immuno-deficiency. Only unusually are they encoun-tered in association with other diseases andonly exceptionally in normal individuals. Pul-monary tuberculosis can obviously present in

immunocompetent individuals but appearswith increased frequency and severity at allimmunological stages of HIV disease in areasof endemic infection.Most of the conditions identified in category

B have been recognised for many years as beingassociated with cell mediated immune defi-ciency of any cause, and more than one ofthese conditions appearing together or sequen-tially should raise suspicion of underlyingimmune deficiency. Investigation must nowalso include assessment for and exclusion ofHIV associated immunodeficiency. In con-trast, bacterial infections with encapsulatedspecies are more typically associated withantibody deficiency states but are also seenwith increased frequency and severity in HIVseropositive subjects. They are particularlyprevalent amongst populations of infecteddrug users where they can be the major causeof morbidity in early HIV infection.'"

Late HIV associated immunodeficiencyClinical presentations in this category areassociated with profound immune deficiencyand comprise a range of opportunistic organ-isms and tumours. Their character and severityof presentation are incompatible with generalor immunological good health. Most present-ing infections or tumours in this category wereincluded in the original case definitions ofAIDS. However, for several years this stage ofdisease has also included 'the severe constitu-tional symptoms of unexplained weight loss,diarrhoea, or fever previously known as AIDSrelated complex, an inevitable harbinger ofsymptomatic immune deficency. Infections inthis category of disease are progressive withoutappropriate treatment. Some, notably Pneumo-cystis carinii, are now largely preventable withprophylactic treatment. This realisation isresulting in increasing enthusiasm for theearlier detection of HIV infection and themonitoring of individuals to determine those atgreatest risk of short term progression, towhom new therapeutic approaches are beingtargeted. Together with the more effectivetherapeutic regimens for established opportu-nistic infections and the use of antiretroviraltreatment, the length of survival of individualsin this category has been substantially length-ened from an initial mean of six months to twoyears or more. However, although longersurvival is now generally achievable continueddisease progression is inevitable in this cat-egory as a result of the severity andirreversibility of the underlying cellular immu-nodeficiency. With the increasing success intreatment of certain infections, there is a risingmorbidity with opportunistic agents which aremore difficult or impossible to treat (cytome-galovirus, atypical mycobacterial infections, orcyptosporidiosis) and a particular tendency forthe development of invasive Kaposi's sarcomaor immunoblastic or Burkitt's type lymphomasas a terminal event. Although lymphomas arereported often (30%) in patients who havebeen receiving long term antiretroviral treat-ment for periods in excess of two years,'2 this

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probably represents a feature of severe longterm immune deficiency rather than a primaryconsequence of treatment with the nucleosideanalogue class of drugs.

Immunological assessment of HIVinfectionA more complete description of the clinicalnatural history of HIV infection has emergedfrom the long term follow up of infectedsubjects, from documented episodes of sero-conversion. Such studies have indicated thatHIV infection is a predictably progressivedisease with a mean incubation time to severesymptomatic disease of about 10 years inyoung adults, irrespective of mode of acquisi-tion of the infection.34 This finding, combinedwith the results of studies and trials suggestingthat prophylactic treatment can delay some ofthe later opportunistic infections, and thatspecific antiretroviral treatment can slow therate of disease progression over intermediatetime periods, have forced a re-evaluation of theneed for earlier identification of HIV infectionand the clinical and immunological assessmentand follow up of the asymptomatic subject.

Following the first detection of HIV infec-tion, the immune status of every individualshould be assessed to guide clinical and ther-apeutic decision making. This is forcing reap-praisal of the long asymptomatic phase of thedisease and is the reason for the introduction ofimmunological subdivisions of this stage ofdisease.

Increasing experimental evidence suggeststhat the early stages of HIV infection aregenerally associated with a strong and partiallyeffective anti-HIV immune response which isassociated with the reduction of initially highlevels of virus replication."3 This state ofrelative immunity can persist for many yearsbut is apparently eroded by the ease with whichHIV mutates away from effective specificantibody and cellular responses.14 However,the observations from natural history studieswhich suggest that immune responses caneffectively suppress viral replication in the earlystages of infection for many years gives hopethat earlier therapeutic intervention may beassociated with considerably enhanced sur-vival.Many immunological parameters are influ-

Table 3 Characteristics of markers ofpotential value in assessment of asymptomatic HIVdisease

B2M CD4 count p24 antigen Viral isolation

Markers present in mostinfected patients(sensitivity) No Yes No Yes

Marker absent fromnon-progressor patients(specificity) Yes Yes Yes No

Change in marker associatedwith disease progression In some Yes In some If quantitated

Marker influenced bytreatment Yes Yes If present ?

Marker directly related todisease pathogenesis No Yes If present Yes

Assay standardisable withquality control Yes Yes Yes ?

Widely available in clinicalcentres Yes Yes Yes No

enced by HIV infection. In the late stages ofdisease virtually every available investigation isabnormal. As the priority for clinical assess-ment is to identify who is most likely toprogress among a pool of asymptomatic indi-viduals and how often follow up assessmentsare required, markers must be chosen whichhave the characteristics given in table 3.

Experience from the classification andassessment of primary immune deficiencystates has indicated that absence of cell popula-tions responsible for immune recognition oreffector responses is usually associated withclinically overt immunodeficiency. However,severe infections can also be seen in associationwith conditions in which loss of specificimmune responses is not necessarily associatedwith deletion of a total cell population. Apply-ing these observations to HIV infection meansthat the deletion of the CD4 cell population,which characterises the late stages of HIVinfection, is associated with severe clinicalimmunodeficiency and complete loss of invitro T cell immune responses. However, inearly HIV infection loss of specific functionalTcell responses generally precede overt evidenceof total CD4 population depletion. There is,therefore, increasing interest in examiningspecific immune responses to characteriseearly evidence of immune compromise inasymptomatic patients to identify those indi-viduals at increasing risk of short term pro-gression.'5

However, such approaches have three majordifficulties. Assays require tissue culture offresh blood lymphocytes, techniques which aredifficult to apply on a large scale; particularlyas containment facilities are required for suchwork. Secondly, such assays are difficult tostandardise and quality control. Finally, thechoice of antigen or polyclonal activator isdifficult. If opportunistic organism antigensare used (the most physiologically relevantapproach) then comparison of patients is aproblem because it is likely that environmentalexposure varies from person to person. Forthese reasons functional assays have not beenwidely evaluated in the longitudinal follow upof individual patients.

Lymphocyte phenotypic markersLaboratory assesment of the degree of immu-nodeficiency generally includes quantitation ofT cell subpopulations. Serum or cellular mark-ers of immune activation give additional infor-mation. Because the destruction of the CD4population is the central lesion of HIV asso-ciated immunodeficiency, severe depletion ofthis T cell subpopulation is an invariablecounterpart of the late stage disease charac-terised by major opportunistic infections.Moreover, several cohort studies have identi-fied that a decline in the CD4 population inHIV seropositive subjects usually identifies asubgroup individual at high risk of short termprogression (table 4). In contrast, individualswith persistently normal or stable CD4 pop-ulations have low rates of short term diseaseprogression.

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Table 4 Incidence ofAIDS in follow-up cohort studies from presentation CD4 count

Presentation CD4 % AIDS incidence atGroup count 3 years Reference

Homosexual < 200 87 3201-400 46

> 400 16Homosexual < 242 68 18

243-345 40346-490 23

> 490 11Injecting drug user < 200 100 19

201-500 51> 500 22

These cohort observations have been largelyresponsible for recommendations that patientswith low presentation CD4 counts or whosecounts fall to low levels on sequential follow upshould receive primary prophylaxis against Pcarinii infection, the most common serious

opportunistic pathogen in late stage HIVinfection. Current advice is that all adults withCD4 counts consistently below 02 x 109Ashould receive such prophylaxis."6

Sequential follow up of asymptomaticpatients has indicated that in most HIV sero-

positive subjects the CD4 count falls pro-gressively with time at an overall rate of about08-1 0 x 109/l/year in cohorts.4 However, therate of fall varies considerably from one indi-vidual to another. Experience suggests thatindividuals with a rapid rate of CD4 cell lossare more at risk of early clinical progression.The relative predictability of clinical progres-sion in individuals showing sequential CD4cell loss has led to increasing interest indirecting specific antiviral treatment at thissubgroup of individuals, although formal trialevidence that early treatment of such asympto-matic subjects results in prolonged overallsurvival is currently lacking.Lymphocyte subpopulation numbers in

blood are notoriously labile, being profoundlyinfluenced by factors which include diurnalrhythm, stress, and intercurrent infection.'7Such considerations determine that trends ofCD4 count stability or progression can only beassessed after a number of estimations havebeen obtained from asymptomatic individualsover a number of follow up attendances. Untila number of data points have been obtained,any assessment based on laboratory investiga-tions alone is unreliable. This considerationprovides a strong argument for the earlyidentification and long term regular followupof the HIV infected subject. During this stageof the disease assessment of T cell markersand CD4 counts, in particular, should only beperformed when patients do not have inter-current infections when spuriously low andmisleading values can be obtained.CD8 counts are also abnormal in most

patients with HIV infection. However, changesin CD8 counts are biphasic. Initial very highabsolute numbers, which are associated withthe immune response to primary HIV infec-tion, gradually fall towards the normal rangemany years later, continuing to fall to sub-normal concentrations in late stage disease.The dynamics of change in CD8 count make it

unreliable as a marker in individual patients.The divergent trends of CD4 and CD8

populations in early HIV disease has resultedin enthusiasm for use of the CD4:8 ratio insome centres. However, as the low ratio char-acteristic of most stages of HIV disease is alsoseen in several other viral infections andchronic immunological diseases, overrelianceon this marker should not be encouraged.Absolute T cell subpopulation numbers pro-vide more reliable staging indices.

Immunological activation markersActivation of lymphocytes, especially CD8cells, is a consistent feature ofmany primary orpersistent viral infections. In HIV infectionsuch activation persists through all stages ofthe disease and affects other lymphoid popula-tions, including B cells. Several markers ofactivation on CD8 cells have been examined,including expression of class II histocompat-ibility antigens (DR), interleukin 2 receptors(CD25), and a number of cell adhesion mol-ecules. Several of these show promise,although they have not been fully evaluated inthe staging of individual patients or in theassessment of response to treatment.Immunological activation results in the

appearance of several lymphocyte and mono-cyte/macrophage products in serum or otherbody fluids. They include cytokines, immuno-globulins, /l2 microglobulin (B2M) and neop-terin. Their relative ease of measurement com-bined with the potential for retrospectiveanalysis on stored serum samples has resultedin considerable interest. Used alone, suchmarkers perform only moderately well partlybecause of low sensitivity and because levelscan also be strongly influenced by other causesofimmune stimulation, of which the infectionscomplicating the later stages of HIV infectionare obvious examples. However, a number ofstudies have shown that when used togetherwith CD4 counts fl2 microglobulin or neopter-in provide additional staging information inindividual patients.'8'20 Raised concentrationsprovide additional power to identify the sub-group of asymptomatic patients at high risk ofclinical progression. Equally significantly, lowconcentrations of fl2 microglobulin, when asso-ciated with relatively normal CD4 counts,identify a subgroup of patients at very low riskof short term clinical progression. Preliminaryevidence suggests that B2M also has potentialas a surrogate marker to assess early benefitfrom HIV specific treatment.2'

Titres of total immunoglobulin classes risedifferentially with different disease stages.Titres of IgA rise with progression to late stagedisease but too late in most individuals to be ofvalue in asymptomatic staging.

Virological markersMethodology which permits quantitation ofcell or plasma HIV viral load will be valuable inthe assessment of disease and treatment.22 23However, such techniques are expensive, poor-ly standardised, and not yet widely available.

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P24 antigen, the only widely applied viralmarker, performs poorly in the asymptomaticpatient where it would be of greatest value asmost such individuals have no detectableantigen. Even in advanced disease, the deter-mination of p24 has poor sensitivity for diseaseprogression. Longer experience suggests thatthis marker does justify the great enthusiasmwith which it was initially associated.

Recommendations for frequency ofclinical and laboratory monitoringAll identified HIV infected subjects should beoffered regular clinical and laboratory followup, irrespective of stage of disease presenta-tion. Progress in understanding of diseasenatural history and evaluation of new treat-ments will require close study of the earlystages of HIV infection.

Initial clinical assessment of asymptomaticsubjects should be accompanied by baselineimmunological investigation. In view of theinherent biological fluctuations associated withthe CD4 count, a further count, irrespective ofthe initial one, is advisable within three monthsto establish baseline values against whichsubsequent trends can be assessed. Suchtrends cannot be extrapolated on the basis ofsingle values for similar reasons and thus allapparent changes in CD4 values should beconfirmed before clinical decisions are taken.For this reason it is advised that the asympto-matic individual is assessed at a minimum ofsix monthly intervals. Evidence of change willrequire more frequent evaluation. f2 micro-globulin and neopterin concentrations shouldbe measured less frequently. As such markersare less labile (but also less sensitive to change)they should be assessed about once a year.

In later stage disease immunological markersbecome progressively less valuable as end-stageprogression approaches. In such patients clin-ical assessment of symptomatology and labor-atory diagnosis of infectious complications arethe major priorities. Once the CD4 count hasfallen consistently below 0-5 x 109/1 in anyindividual then further assessment is probablyonly justifiable to assess therapeutic responseto new antiviral agents.

Future prospectsThe new CDC/WHO classification of HIVdisease will probably change perceptions asattention is shifted from late to early stagedisease. Moreover, the pace of assessment ofnew therapeutic approaches is already slowedby the widespread introduction of partiallyeffective treatments in later stage disease,delaying the appearance of clinical endpointsin clinical trends. Future clinical trials arelikely to become increasingly reliant on theenrolment of asymptomatic patients withassessment of efficacy based on the use ofsurrogate immunological or virological mark-ers. Following initial evaluation of such trials itis likely that such laboratory monitoring will

become increasingly valuable in the clinicaldecisions about when such agents should beused. For any such laboratory investigations tobe widely acceptable internal and externalquality control and standardised methodolo-gies will be essential prerequisites.

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