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HIV infection and AIDS

ANDREW LLOYD1

Prince Henry Hospital and Prince of Wales Hospital, Sydney, Australia

SUMMARY

Many of the clinical features of HIV/AIDS can be ascribed to the profound immunedeficiency which develops in infected patients. The destruction of the immune system by thevirus results in opportunistic infection, as well as an increased risk of autoimmune disease andmalignancy. In addition, disease manifestations related to the virus itself may occur. Forexample, during the primary illness which occurs within weeks after first exposure to HIV,clinical symptoms occur in at least 50% of cases, typically as a mononucleosis syndrome. HIV-related complications are rarely encountered in patients with preserved immunity (i.e. CD4 T-cell counts greater than 500 cells/mm3). Recurrent mucocutaneous herpes simplex (HSV),herpes zoster (VZV), oral candidiasis and oral hairy leukoplakia occur with increasingfrequency as the CD4 count drops below this level. Immune thrombocytopenia (ITP) occurs inassociation with HIV and often presents early in the clinical course. The risk of developingopportunistic infections and malignancies typical of AIDS increases progressively as CD4counts fall below 200 cells/mm3. The clinical manifestations of infections associated with AIDStend to fall into well-recognized patterns of presentation, including pneumonia,dysphagia/odynophagia, diarrhoea, neurological symptoms, fever, wasting, anaemia andvisual loss. The commonest pathogens include Candida albicans, Pneumocystis carinii,Mycobacterium tuberculosis, Toxoplasma gondii, Cryptococcus neoformans, Mycobacteriumavium intracellulare and cytomegalovirus. Malignant disease in patients with HIV infectionalso occurs in a characteristic pattern. Only two tumours are prevalent: Kaposi’s sarcoma, amultifocal tumour of vascular endothelium which typically involves skin and mucosalsurfaces; and non-Hodgkin’s lymphoma, which is typically high grade in phenotype, oftenarising within the central nervous system. The principles of therapy include reduction of HIVreplication by antiretroviral agents, prophylaxis against the common opportunistic infectionsand treatment followed by subsequent lifelong maintenance therapy for infections when theydo occur.

It is estimated that approximately 20 millionpeople worldwide will have been infected withthe human immunodeficiency virus (HIV) bythe turn of the century. Unfortunately, almostevery country in the globe, including PapuaNew Guinea, now has growing numbers ofcases of HIV/AIDS. Undoubtedly theparamount issue for Papua New Guinea inrelation to the HIV epidemic is rapid,widespread and effective public educationabout HIV and other sexually transmitteddiseases. This review focuses on the clinicalfeatures of the illnesses associated with HIVinfection. For further information see Stewart(1) and Gold et al. (2).

The virus and the immune system

The human immunodeficiency virus is thecause of the acquired immune deficiencysyndrome (AIDS). The virus belongs to arecently discovered family of small RNAviruses, the retroviruses, whose unique featureis the mechanism of replication (RNA to DNA,rather than the converse) via a virally encodedenzyme, reverse transcriptase. The retroviruses,including HIV, are transmitted ‘vertically’from mother to infant, and ‘horizontally’ viasexual intercourse and blood-to-blood contact(Table 1). Although HIV has been isolatedfrom saliva, tears, urine and cerebrospinal

1 Director, AIDS Unit, Prince Henry/Prince of Wales Hospitals, Sydney, NSW, Australia

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TABLE 1

TRANSMISSION OF HIV

Sexual intercourse Vaginal intercourseAnal intercourse

Contaminated needle or syringe Reused needles or syringesNeedlestick injuriesShared injecting apparatus

Blood, organ or tissue donation Blood products(if not screened) Semen

KidneysSkin, bone marrow, cornea, heart valves,

tendons etc

Mother to child In uteroAt birthBreastmilk

TABLE 2

CLINICAL CLUES TO HIV INFECTION

Common disorders which are Herpes zosterincreased in prevalence with HIV Molluscum contagiosuminfection Seborrhoeic dermatitis

Recurrent herpes simplex infectionGingivitisCervical intraepithelial neoplasia (CIN)

Uncommon disorders suggestive of Oral candidiasisHIV infection Immune thrombocytopenia

Guillain-Barré syndromeTuberculosisCryptococcal meningitisDementiaNon-Hodgkin’s lymphoma

Uncommon disorders highly Oral hairy leukoplakiasuggestive of HIV infection Kaposi’s sarcoma

Pneumocystis carinii pneumonia (PCP)Cerebral toxoplasmosisOesophageal candidiasisMycobacterium avium complex (MAC)Cytomegalovirus (CMV) infection

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fluid, the concentration is very low. Hence,transmission from these fluids is extremelyunlikely.

Many of the clinical features of HIVinfection can be ascribed to the profoundimmune deficiency which develops in infectedpatients. The cellular target for HIV is thesurface protein called CD4, found onperipheral blood T lymphocytes (and to alesser extent other cells in the skin, gut, brainetc). Thus progressive depletion of CD4+ Tlymphocytes is the characteristic feature of theadvancing immune deficiency in patients withHIV and AIDS. CD4 T cells are a criticalcomponent of the immune system. These cellsregulate the synthesis of antibodies, orchestratethe killing of intracellular microorganisms andtumour cells by regulating the activity ofcytotoxic T cells, and control the function ofnonspecific effector cells of the immunesystem, including macrophages andneutrophils. Thus it is the complications ofimmune deficiency (infection, tumourdevelopment and autoimmunity), rather thanthe direct effects of HIV itself, whichpredominate in the clinical manifestations ofAIDS.

Diagnosis of HIV infection

The diagnosis of HIV-related illnesses in thepatient presenting to general practice reliesheavily on the history of risk factors for HIVtransmission (Table 1), on the lifestyle history,and on the detection of clinical cluessuggestive of HIV infection (Table 2).

The HIV antibody test is the key toconfirmation of HIV infection. If the patient isaware of HIV/AIDS and has someunderstanding of its significance then it isimportant that, before an antibody test isordered, the physician allows time to explainthe testing process and the implications of apositive result. However, in Papua New Guineavery few patients (especially in the villagesetting) currently have enough prior knowledgeto allow truly informed consent for an HIVantibody test. The physician and the patientshould be aware that confirmatory tests in areference laboratory are necessary if an initialpositive result is obtained, and hence definitiveresults may take several weeks to becomeavailable.

Laboratory testing for HIV is primarilybased upon detection of antibodies directedagainst the virus. In Papua New Guinea, themost commonly used screening test is a gelparticle agglutination assay (SerodiaFujirebio). If the initial test is positive then it isfirst confirmed by a repeat in the same assay,followed by confirmatory testing, which isusually done by enzyme-linked immunoassayin the National Reference Laboratory.

Primary HIV infection

After first exposure to HIV there is a periodof two to four weeks in which viral replicationis high, there is little evidence of immuneresponse, and the virus becomes establishedwithin lymph nodes and other sites includingthe central nervous system. This primaryillness is associated with clinical symptoms inat least 50% of cases, typically as amononucleosis syndrome (Table 3). Thedifferential diagnosis of the primary HIVillness includes viral hepatitis, Epstein-Barrvirus or cytomegalovirus (CMV) infection,rubella, other viral infections, secondarysyphilis and toxoplasmosis.

Ongoing management of the patient with HIV

After initial exposure to the virus, the courseof HIV infection thereafter varies significantlybetween patients. Over 10 years, approximately50% of patients will develop significantimmune deficiency and associatedopportunistic infections or tumour, marking theonset of AIDS. This interval from infection tothe advent of AIDS may be as short as months,or perhaps as long as 20 years or more.

A patient who has a positive HIV diagnosisshould have baseline investigations seeking todefine relevant co-morbidity including a bloodcount and differential, and renal and liverfunction tests. Where appropriate, evidence forother blood-borne or sexually transmittedinfections should be sought, such as hepatitis Band C, and syphilis. Assays for IgG antibodiesagainst toxoplasmosis and CMV may behelpful (as these infections may reactivate andproduce disease later in the clinical course).Monitoring the number of peripheral bloodCD4 T lymphocytes provides a reasonablepicture of the current risk of opportunisticinfection and may guide specific prophylactic

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and antiretroviral therapy. However, thisexpensive technology is restricted to developedcountries, and is not available in Papua NewGuinea. Therefore clues regarding the extent ofimmune deficiency should be sought fromclinical features. For example, the first adventof oral candidiasis or recurrent herpes genitalisimplies early immunodeficiency, whereasCMV retinitis typically occurs when there isprofound loss of T cell numbers. In addition, adifferential white cell count may be used toenumerate the number of peripheral bloodlymphocytes. Even allowing for the uncertainnumber of the subpopulations (CD4+ T cells,CD8+ T cells and B cells), the presence of atotal lymphocyte count of 500 cells/mm3(µl) orless in an HIV-positive patient is highly likelyto indicate significant immunodeficiency.

Early signs of HIV infection are usuallyrelated to the virus itself (Table 4) andfrequently occur before any significant immunedeficiency has developed; for example, theCD4 count may still be in the normal range of700-1500 cells/mm3(µl).

For the asymptomatic patient, who has noclinical or laboratory clues to immuno-deficiency or complicating illness, outpatientvisits should be routinely arrangedapproximately every three months, and shouldinclude a physical examination and bloodcount with a differential.

Symptomatic HIV infection

HIV-related complications are rarely

TABLE 3

CLINICAL FEATURES OF PRIMARY HIV INFECTION

General

FeverPharyngitisLymphadenopathyArthralgia and myalgiaFatigueAnorexia and weight loss

Dermatological

Erythematous maculopapular rashUrticariaDesquamationAlopecia

Neurological

HeadacheMeningoencephalitisPeripheral neuropathyRadiculopathyGuillain-Barré syndromeCognitive or mood change

Gastrointestinal

Mucocutaneous ulcerationOropharyngeal candidaNausea and vomitingDiarrhoea

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encountered in patients with CD4 T-cell countsgreater than 500 cells/mm3(µl). Recurrentmucocutaneous herpes simplex (HSV), herpeszoster (VZV), oral candidiasis and oral hairyleukoplakia may occur when the lymphocytenumber starts to fall. Oral acyclovir is effectivein the treatment and prophylaxis of herpessimplex infections, and the treatment of herpeszoster. Oral candidiasis will usually respond totopical antifungal therapies including nystatin,amphotericin or miconazole. Immunethrombocytopenia (ITP) occurs in associationwith HIV and often presents early in theclinical course. Effective therapies includeantiretroviral treatment with zidovudine,corticosteroids and splenectomy.

The risk of developing opportunisticinfections and malignancies typical of AIDSincreases progressively as CD4 counts fallbelow 200 cells/mm3. At this stage the use ofprophylactic antimicrobials to prevent or delaythe onset of infections has been shown to beeffective (Table 5).

The clinical manifestations of infections or

malignancies associated with AIDS tend to fallinto well-recognized patterns of presentation(Table 6). The investigation and managementof these complications will typically requirereferral to a specialist service. As tuberculosisand cryptococcosis are relatively commoninfections in Papua New Guinea and areknown to be associated with HIV infection,these two infections are likely to dominate theclinical picture of AIDS in PNG. In addition,as recurrent Salmonella bacteraemia iscommon in patients with HIV/AIDS, thoseareas of PNG where typhoid is prevalent arelikely to find this infection commonly inpatients with HIV. Equally important is thepotential for the growing numbers of HIV-infected patients to provide a reservoir fortransmission of tuberculosis and typhoid tonon-HIV-infected individuals.

Treatment of AIDS-related infections isfrequently divided into a phase of therapydesigned to control the infection (with apparenteradication of the organism), followed by amaintenance regimen intended to preventrelapse, which is common if ongoing therapy is

TABLE 4

CLINICAL FEATURES OF PATIENTS WITH EARLY HIV INFECTION

Constitutional Fevers, malaise, fatigue, night sweats, lymphadenopathy, diarrhoea, unexplainedweight loss

Dermatological Recurrent herpes simplex, facial seborrhoeic dermatitis, molluscum contagiosum,folliculitis, impetigo, shingles

TABLE 5

PROPHYLAXIS AGAINST AIDS-RELATED OPPORTUNISTIC INFECTIONS

Pneumocystis carinii pneumonia (PCP) CotrimoxazoleDapsone and trimethoprimNebulized or intravenous pentamidine

Oral or oesophageal candida KetoconazoleFluconazole

Recurrent mucocutaneous herpes simplex Acyclovirvirus (HSV) infection

Disseminated Mycobacterium avium Rifabutincomplex (MAC)

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not undertaken. Standard combinationantituberculous therapy has been shown to beeffective for patients with HIV and TB,although the relapse rate is significantly higherthan in non-HIV-infected patients. Similarly,standard antifungal therapy for cryptococcalmeningitis is effective for patients with HIVand cryptococcosis. In Papua New Guinea,emphasis in patient care should be placed ondiagnosis and management of the majortreatable conditions associated with HIV:tuberculosis, cryptococcosis and salmonella

infections; as well as the more common minorinfections – oro-oesophageal candidiasis andrecurrent herpes simplex.

Malignant disease in patients with HIVinfection also occurs in a characteristic pattern.Only two tumours are prevalent – Kaposi’ssarcoma and non-Hodgkin’s lymphoma.Squamous cell carcinoma of the anogenitalarea and cervix, and basal cell carcinoma of theskin are also found with increased frequency.Kaposi’s sarcoma appears to be a tumour of

TABLE 6

PATTERNS OF CLINICAL PRESENTATION IN AIDS

Presentation Common causes Investigations

Pneumonia Pneumocystis carinii Chest X-rayPneumococcus Sputum examinationHaemophilus influenzae Sputum cultureTuberculosis

Dysphagia, Candidiasis Endoscopy and biopsyodynophagia CMV

HSVKaposi’s sarcoma

Diarrhoea Cryptosporidia Stool microscopy and cultureMicrosporidia Sigmoidoscopy and biopsyMACCMVHIV enteropathy

Neurological Cryptococcosis Lumbar puncturesymptoms Toxoplasmosis

LymphomaHIV encephalitisPML

Fever, wasting, Tuberculosis Sputum, stool or blood cultureanaemia Salmonellosis Bone marrow biopsy and culture

MAC Lymph node biopsyCMVLymphoma

Visual loss CMV Ophthalmological review

CMV CytomegalovirusHSV Herpes simplex virusMAC Mycobacterium avium complexHIV Human immunodeficiency virusPML Progressive multifocal leucoencephalopathy

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vascular endothelial cells, is often multicentric,is nonmetastasizing and rarely involves thecentral nervous system. The lesions aretypically mucocutaneous, appear as purple orbluish-brown papules, and may accumulate toseveral hundred in number. High grade non-Hodgkin’s lymphomas of B-cell origin arerelatively common in patients with AIDS.These lymphomas are strongly associated withEpstein-Barr virus infection in the tumour, mayoccur with a primary focus in the centralnervous system, and generally have a poorprognosis.

In addition to opportunistic infections andtumours, patients with HIV infection aresusceptible to neurological disorders directlyattributable to the neurotropic character ofHIV. Early in the clinical course, asepticmeningitis and peripheral neuropathy mayoccur. As the HIV infection advances, asubacute dementia referred to as the AIDSdementia complex (ADC) may develop.Although this syndrome may occur at a timewhen significant immune deficiency has notyet developed, typically ADC happens late inthe AIDS illness. ADC is characterized by aprogressive cognitive deterioration inassociation with ataxia, wasting and weakness,as well as urinary incontinence. The onlytherapy shown to slow the progression of ADCis the antiretroviral agent, zidovudine.

Antiretroviral therapy

Antiretroviral agents are commonlyprescribed for patients with HIV/AIDS. Thesubstantial cost of each of these drugs hasprohibited their widespread use in developingcountries. Zidovudine (ZDV, formerly knownas AZT), didanosine (dideoxyinosine; ddI) andzalcitabine (dideoxycytidine; ddC) are the threeagents currently licensed for use in manycountries. Each of these agents has been shown

to inhibit HIV replication by inhibition ofreverse transcription. They improve CD4 cellcounts and reduce the likelihood ofopportunistic infections developing in patientswith HIV infection. ZDV, the first drugevaluated, has been shown to prolong survivalin patients with AIDS and also to delay theprogression to AIDS in patients with HIVinfection.

A growing body of evidence suggests thatcombination therapy with these agents andwith newer drugs with different modes ofinhibition of HIV activity is likely to be thefuture standard therapy. It remains unclear asto the ideal timing for the initiation ofantiretroviral treatment. Current practice rangesfrom treatment commenced when the CD4 cellcount falls below 500 cells/mm3 to deferringtherapy until CD4 counts are as low as 300cells/mm3 and HIV-related symptoms havedeveloped. ZDV alone, or combinations ofZDV with ddI or ddC, may be prescribed.

Multiple newer drugs which target otherstages of the replicative cycle of HIV havebeen developed, many with potent antiviraleffects. These drugs include the inhibitors ofHIV protease. It is hoped that in combinationwith existing and novel antiretroviral agentsthese drugs will provide a treatment strategy toallow long-term control of HIV disease.

REFERENCES

1 Stewart G, ed. Could It Be HIV? The ClinicalRecognition of HIV Infection, 2nd edition.Sydney: Australasian Medical PublishingCompany, 1994.

2 Gold J, Penny R, Ross M, Morey S, Stewart G,Donovan B, Berenger S, eds. The AIDS Manual.A Comprehensive Reference on the HumanImmunodeficiency Virus (HIV), 3rd edition.Sydney: MacLennan and Petty, 1994.