HIV/AIDS

The Centers for Disease Control Clinical Staging System for HIV
This is a common staging system which essentially details four mutually exclusive categories or groups of HIV infection as shown in Table. Every individual does not have to progress through all the stages but it is hierarchical i.e. having reached a particular stage, reversion to an earlier stages if the signs or symptoms settle does not occur. Table 1 Classification of effects of HIV infection CDC Stage Clinical Description I acute infection with seroconversion II asymptomatic infection III persistent generalised lymphadenopathy IV Symptomatic HIV disease IV A constitutional symptoms and disease IV B neurological disease IV C immunodeficiency IV C1 1982 CDC definition of AIDS IV C2 infections out with AIDS definition IV D tumours in CDC definition of AIDS IV E Other e.g. Hodgkins, carcinoma, lymphoid interstitial pneumonia, symptomatic thrombocytopenia

WHO staging system

Until recently the CDC classification was the only viable clinical classification system used to stage HIV. The WHO introduced a staging system which utilises 4 clinical stages (see Appendix). The WHO and CDC then came up with a combined staging system and it is possible that with the increasing use of CD4 counts this new WHO/CDC classification system will be utilised in its place. The new system essentially consists of three broad clinical stages, well or asymptomatic, HIV related diseases and AIDS combined with three stages of immunodeficiency as measured by either CD4 counts (>500 cell/cumm, 200-500 and < 200) or lymphocyte counts. When combined in a three way table there are thus 9 possible stages. In the USA everyone with a CD4 count below 200 is to be classified as AIDS although this is not the case for Europe at present. Table 2 WHO/CDC classification system for HIV Laboratory Classification Absolute CD4 count 1 2 3 >500/cumm 200-499/cumm <200/cumm or Total lymphocyte count (TLC) >2000/cumm 1000-1999/cumm < 1000/cumm

Clinical Category* A A1 A2 A3 B B1 B2 B3 C C1 C2 C3

*Definitions of Clinical Groups for Table 1.2 Clinical category A (Asymptomatic disease) Acute infection with HIV; persistent generalised lymphadenopathy; asymptomatic. Conditions in Groups B and C must be absent. Clinical category B (Symptomatic disease) Any symptomatic conditions not included in Category C. Examples are bacterial infections, candidiasis (oral or vulvovaginal) for >1 month, cervical dysplasia or carcinoma, constitutional symptoms,oral hairy leukoplakia. Two distinct episodes of herpes zoster or involving more than one dermatome, idiopathic thrombocytopenia purpura, mycobacterium tuberculosis,peripheral neuropathy. Clinical category C Any condition which meets the 1987 CDC/WHO case definition for AIDS.

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HIV staging and definitions

1992 Definition of AIDS

The CDC also proposed that three new clinical problems be added to the 1987 definition of AIDS. These are cervical cancer two episodes of bacterial pneumonia in a 12 month period pulmonary tuberculosis. These new clinical definitions of AIDS have been added to the UK definition but not any definition based on CD4 counts.

Progression from HIV to AIDS

The exact explanation for progression from early HIV to AIDS is unknown. A number of possible markers have been associated with progression including low numbers of CD4 lymphocytes (a figure of less than 200 suggests that 50% will progress in 2 years) immune thrombocytopenic purpura, high levels of -2microglobulin and IgA, low haemoglobin (or hematocrit) and the level of viral RNA (viral load) in the blood. The most important cofactors associated with progression to date are age (increasing age hastens progression) and HLA type - A1 B8 DR3 is associated with fast progression and B27 with slow progression. In Edinburgh there was a strong HLA (A1-B8-DR3) association with faster progression and relative risks of 3.8 (CI 1.9-7.5), 3.1 (1.6-6.0) and 2.0 (1.2-3.4) for the endpoints of death, AIDS and CDC stage IV respectively. Gender and risk activity seem less important. Rates of progression from HIV to AIDS (1987) 2 yrs 4 yrs 6 yrs 8 yrs 10yrs 0-2% 5-10% 10-25% 30-40% 51%

Median time for progression from infection to AIDS has now risen to 11-12 years. Another way to look at progression is to consider the risk for the patient which is on average 8% per year Rates of progression according to CD4 count > 500 350-500 200-350 < 200 1%/yr 3%/yr 10-12%/yr 20%/yr

The decline in CD4 counts can be predicted. In Edinburgh the CD4 cell loss was approximately linear when transformed to the square root scale with a slope of -1.56 (SD 0.94) per annum as was the decline in CD4% with a slope of -1.44 %(SD 0.88) per annum. HLA effects on slopes were found: A1-B8-DR3 was significantly associated with faster loss of both absolute CD4 cells and CD4% (p=0.00) and B27 was significantly associated with slower loss of CD4% (p=0.01). There were 2.5% of the group with no decline or an actual increase in their CD4 counts (non progressors) and depending upon the definition applied between 11 and 28% with slow decline in CD4 counts (slow progressors: slope greater than -0.5).

Pre-AIDS death
In drug users AIDS cases greatly under represent serious HIV disease. In New York, there was a rapid increase in both AIDS and non AIDS narcotic related deaths. By 1986, for every AIDS related death in a drug user, there was one other as a consequence of such conditions as tuberculosis, endocarditis and bacterial pneumonia. Similar data from other centres. Pre-AIDS death rate in drug users is around 2-2.5% per year compared to 0-0.5% in other risk groups.

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Survival after AIDS

Whilst this has improved from around 6 months, even now only around 50% of patients with AIDS survive one year. Survival after AIDS is also worsened by increasing age and HLA haplotype A1 B8 DR3. In Edinburgh the relative risk was 2.5 (CI 1.1-5.8) 1yr 2yrs 3-4yrs 5yrs 50% 25% 5% 0%

Survival from a CD4 count of 200 is better for the early years - 5 year survival is between 30-50%. In our own experience the median survival for the 1987 definition of AIDS is 20 months but 40 months for CD200 to death (as defined by 2 counts below 200). The 1992 definition of AIDS (one count below CD200) has a median survival of 50 months. Survival rates are respectively at 2 years 42% (1987 AIDS), 71% (CD200x2) and 80% (CD200x1).

Effect of risk group on presentation

Little variation but conditions such as KS unusual in the absence of homo/bisexuality or sexual contact with a case. KS, cytomegalovirus and cryptosporidiosis are all significantly less common in drug users while PCP, Tuberculosis, oesophageal candidiasis and extra-pulmonary Cryptococcosis are more common.

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HIV staging and definitions

Appendix The surveillance definitions of AIDS (1987)

The Centers for Disease Control, Atlanta produced a revised definition of AIDS in 1987 which is as follows. I. Without laboratory evidence of HIV infection. If laboratory tests for HIV are not available then provided the following conditions (under IA) are not present a diagnosis of AIDS can be made provided the disease is diagnosed definitively (under IB). IA. Causes of immunodeficiency that disqualify diseases as indicators of AIDS in the absence of evidence of HIV infection. 1. High dose or long term systemic corticosteroid therapy or other immunosuppressive/cytotoxi therapy for < or = 3 months before the onset of the indicator disease. 2. Any of the following disease diagnosed for < or = 3 months after the diagnosis of the indicator disease: Hodgkin's disease, non- Hodgkins lymphoma (other than primary brain lymphoma), lymphocytic leukaemia, multiple myeloma, any other cance of the lymphoreticuar or histiocytic tissue, or angioimmunoblastic lymphadenopathy. 3. A genetic (congenital) immunodeficiency syndrome or an acquired immunodeficiency syndrome atypical of HIV infection, such as one involving hypogammaglobulinaemia. IB.Indicator disease diagnosed definitively: 1. Candidiasis of the oesophagus, trachea, bronchi, or lungs. 2. Cryptococcosis, extrapulmonary. 3. Cryptosporidiosis with diarrhoea for > 1 month. 4. Cytomegalovirus disease of an organ other than the liver, spleen, or lymph nodes in a patient > or = 1 month of age. 5. Herpes simplex virus infection causing a mucocutaneous ulcer that persists for > 1 month; or bronchitis, pneumonitis, or oesophagitis for any duration affecting a patient > or = 1 month of age. 6. Kaposi's sarcoma affecting a patient < or = 60 years of age. 7. Lymphoma of the brain (primary) affecting a patient < or = 60 years of age. 8. Lymphoid interstitial pneumonia and or pulmonary lymphoid hyperplasia (LIP/PLH) complex affecting a child less than or equal to 12 years of age. 9. Mycobacterium avium complex or M.kansasii disease, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes). 10. Pneumocystis carinii pneumonia. 11. Progressive multifocal leukoencephalopathy. 12. Toxoplasmosis o the brain affecting a patient > or = 1 month of age. II.With laboratory evidence of HIV infection. Regardless of the presence of other causes of immunodeficiency outlined above (under IA), in the presence of laboratory evidence of HIV infection, any disease listed above (under IB) or below (under IIA or IIB) indicates a diagnosis of AIDS. IIA.The following conditions, diagnosed definitively; 1. bacterial infections, multiple or recurrent (any combination of at least two within a 2-year period), of the following types affecting a child <13 years of age: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media or superficial skin or mucosal abscesses), caused by Haemophilus, Streptococcus (including pneumococcus), or other pyogenic bacteria. 2. coccidioidomycosis, disseminated (at a site other than or in addition to lungs of cervical of hilar lymph nodes). 3. HIV encephalopathy (also called "HIV dementia", "AIDS dementia", or "subacute encephalitis due to HIV"). 4. histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes). 5. isosporiasis with diarrhoea persisting >1 month. 6. Kaposi's sarcoma at any age. 7. lymphoma of the brain (primary) at any age. 8. other non-Hodgkin's lymphoma of B-cell or unknown immunologic phenotype and the following histologic types: 9. a.small noncleaved lymphoma (either Burkitt or non- Burkitt type).

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10. b.immunoblastic sarcoma (equivalent to any of the following, although not necessarily all in combination: immunoblastic lymphoma, large-cell lymphoma, diffuse histiocytic lymphoma, diffuse undifferentiated lymphoma, or high grade lymphoma). 11. Note: Lymphomas are not included here if they are of T-cell immunological phenotype or their histological type is not described or is described as "lymphocytic", "lymphoblastic", "small cleaved", or "plasmacytoid lymphocytic". 12. any mycobacterial disease caused by mycobacteria other than M. tuberculosis, disseminated (at a site other than or in addition to lungs, skin or cervical or hilar lymph nodes. 13. disease caused by M. tuberculosis, extrapulmonary (involving at least one site outside the lungs, regardless of whether there is concurrent pulmonary involvement. 14. Salmonella (nontyphoid) septicemia, recurrent. 15. HIV wasting syndrome (emaciation, "slim disease"). IIB.The following conditions, diagnosed presumptively; 1. Candidiasis of the oesophagus. 2. Cytomegalovirus retinitis with loss of vision. 3. Kaposi's sarcoma. 4. Lymphoid interstitial pneumonia and or pulmonary lymphoid hyperplasia (LIP/PLH) affecting a child < or = 13 years of age. 5. Mycobacterial disease (acid-fast bacilli with species not identified by culture), dissemonated (involving at least one site other than or in addition to lungs, skin, or cervical or hilar lymph nodes). 6. Pneumocystis carinii pneumonia. 7. Toxoplasmosis of the brain affecting a patient > or = to 1 month of age. III. With laboratory evidence against HIV infection. With laboratory test results negative for HIV infection, a diagnosis of AIDS for surveillance purposes is ruled out unless: A.All the other causes ofimmunodeficiency listed above are excluded and B.The patient has had either: 1. Pneumocystis carinii pneumonia diagnosed by a definitive method or 2. a. any of the other disease indicative of AIDS listed above diagnosed by a definitive method and b. a CD4 count of less than or equal to 400 cells/cumm.

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HIV staging and definitions

WHO Clinical Classification System WHO Asymptomatic WHO Stage 1

This includes the acute retroviral syndrome of initial infection, the asymptomatic and those with persistent generalised lymphadenopathy.

WHO Symptomatic
This has been divided into two areas;

WHO Stage 2
Weight loss < 10% of body weight Mucocutaneous manifestations such as seborrhoeic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations, angular cheilitis. Herpes zoster Recurrent upper respiratory tract infections such as bacterial sinusitis.

WHO Stage 3
Weight loss > 10% of body weight Unexplained chronic diarrhoea > 1 month. Unexplained prolonged fever (intermittent or constant > 1 month. Candidiasis, oral. Candidiasis, vulvovaginal for > 1 month Oral hairy leukoplakia. Pulmonary tuberculosis. Severe bacterial infections such as pneumonia or pyomyositis. Bed ridden for < 50% ofthe day during the last month. WHO - AIDS

WHO stage 4
Bed ridden for > 50% of the day during the last month. Candidiasis of the oesophagus, trachea, bronchi or lungs. Cryptococcus, extrapulmonary Cryptosporidiosis with diarrhoea for > 1 month. Cytomegalovirus disease of an organ other than the liver, spleen or lymph nodes. Herpes simplex infection, mucocutaneous for > 1 month or visceral for any duration. HIV dementia (encephalopathy). Isosporiasis with diarrhoea for > 1 month. Kaposi's sarcoma Lymphoma Mycobacterium tuberculosis - extrapulmonary Mycobacteriosis- atypical and disseminated. Mycosis - disseminated histoplasmosis or coccidioidomycosis. Pneumocystis carinii pneumonia. Progressive multifocal leukoencephalopathy. Salmonella septicaemia (non-typhoidal) Toxoplasmosis of the brain. Wasting syndrome due to HIV.

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HIV staging and definitions