جهاد عرفات
25-04-2006, 01:05 PM
Classification of HIV disease can be undertaken for several purposes and should be distinguished from disease staging. Staging is disease classification that aims primarily to make groupings that have different prognosis and can be used in guiding treatment decisions. Stages attempt to classify disease in a progressive sequence from least to most severe, each higher stage having a poorer prognosis or different medical management than the preceding stage. Early in the AIDS epidemic, clinical manifestations were frequently categorized as those diagnoses meeting the surveillance case definition of AIDS and other less severe signs and symptoms collectively known as AIDS-related conditions or complex (ARC). As more became known about the full spectrum of HIV-related disease, the term ARC was largely abandoned and the pathologic process from HIV infection to symptomatic disease was characterized with the more comprehensive phrase "HIV disease." A number of classification and staging systems have been proposed for HIV disease, most using a combination of the CD4 lymphocyte count and symptoms, but only the classification scheme constructed by the Centers for Disease Control and Prevention (CDC) has gained wide acceptance.
The CDC Classification Scheme for HIV Disease
The CDC classification of HIV disease was first put forth as a categorization of HIV-related symptoms into four groups and was explicitly for "public health purposes" and not "intended as a staging system,"(1) although it was frequently treated as if it were a staging system in the AIDS literature. The current CDC classification system, from the revision in 1993, combines three categories of the CD4 count with three symptom categories and is closer to a staging system but is still not described as such.(2) The CDC, however, proposed that it be used to "guide clinical and therapeutic actions in the management of HIV-infected adolescents and adults."(2) This de******ion of its intended use is close to the use of a staging system. The categories are shown in Table 1.
The definitions of the three CD4+ T-lymphocyte categories and the three categories of clinical conditions used in Table 1 follow:
• Category 1: > 500 cells/mm3 (or CD4% > 28%)
• Category 2: 200-499 cells/mm3 (or CD4% 14% - 28%)
• Category 3: < 200 cells/mm3 (or CD4% < 14%)
These categories correspond to CD4+ T-lymphocyte counts per microliter of blood. The percentage of CD4+ T cells can be substituted for the count as indicated in parentheses. The lowest accurate, but not necessarily the most recent, CD4+ T-lymphocyte count or percentage should be used for classification purposes. The percentages were derived from correlating counts and percentages from 7 data sources. The correspondence of a 200 count to 14 percent showed little variation (range from the 7 data sources: 13 to 14%), but the correspondence of a 500 count to 29 percent was more variable (range from the 7 data sources: 22.5 to 39%).(2)
Category A
Category A consists of one or more of the conditions listed below in an adolescent or adult (> 13 years) with ********ed HIV infection. Conditions listed in Categories B and C must not have occurred.
• Asymptomatic HIV infection
• Persistent generalized lymphadenopathy
• Acute (primary) HIV infection with accompanying illness or history of acute HIV infection
Category B
Category B consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical Category C and that meet at least one of the following criteria: (a) the conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or (b) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples of conditions in clinical category B include but are not limited to:
• Bacillary angiomatosis
• Candidiasis, oropharyngeal (thrush)
• Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy
• Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
• Constitutional symptoms, such as fever (38.5 degrees centigrade) or diarrhea lasting greater than 1 month
• Hairy leukoplakia, oral
• Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome
• Idiopathic thrombocytopenic purpura
• Listeriosis
• Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess
• Peripheral neuropathy
For classification purposes, Category B conditions take precedence over those in Category A. For example, someone previously treated for oral or persistent vaginal candidiasis (and who has not developed a Category C disease) but who is now asymptomatic should be classified in Category B.
Category C
Category C includes the clinical conditions listed in the 1993 AIDS surveillance case definition (see subsequent section) For classification purposes, once a Category C condition has occurred, the person will remain in Category C.
CD4 lymphocyte count or the CD4 lymphocyte percentage is generally acknowledged to follow closely the progression of HIV immunosuppression, and the CD4 lymphocyte count is currently the principal laboratory test used in clinical management of HIV infection. Recommendations for both antiviral therapy and prophylaxis of opportunistic infections are ****d on CD4 lymphocyte count or percent. Frequent AIDS diagnoses, such as PCP, are uncommon at CD4 counts above 200/mm3,(3) and other AIDS-defining conditions, such as toxoplasmosis and non-Hodgkin's lymphoma, typically occur at even lower CD4 counts. The CDC 1993 revision of the classification of HIV disease makes the three levels of CD4 lymphocyte count (0-199, 200-499, 500 and greater) central. The choice of those categories was strongly influenced by treatment recommendations at the time of the revision in 1993 to initiate antiretroviral therapy when the CD4 count fell below 500 and to initiate PCP prophylaxis when the count fell below 200. The choice of a CD4 count at 500 as one of the classifying strata is in part an artifact of strata chosen for clinical trials of antiretroviral treatments in the United States and has not been followed by some trials outside the United States that have used a stratum below 400 per microliter.(4) Many of the staging systems discussed below have used a stratification at 400 cells.
Although the 1993 classification system provides a better categorization of HIV disease than the 1986 system by groups that have generally increasing immunosuppression, its inadequacy as a staging system can be seen in the lack of a clear progression of disease severity for each of the nine categories. An individual in group A3 has AIDS by the current CDC surveillance definition even though asymptomatic and probably has a poorer prognosis than an individual in group B1 with oral candidiasis and a CD4 count of 500 per microliter. Although individuals in group A1 probably have the best prognosis in general and those in group C3, the worst, the other groups are less clearly distinguished by disease severity and prognosis.
Because the 1986 CDC HIV classification was used frequently in the AIDS literature and many studies used the 1986 Group IV disease as a clinical outcome variable, the 1986 classification scheme is shown in Table 2.(1)
The 1986 classification system as a staging system had problems similar to the 1993 revision, but it allowed for much greater inconsistency in the categories considered as disease stages because CD4 lymphocyte count was not used and persistent generalized lymphadenopathy was given a separate category (Group III). Natural history studies have failed to distinguish persons with persistent generalized lymphadenopathy from asymptomatic persons by their risk of AIDS or their CD4 lymphocyte counts and the 1993 classification system acknowledges this lack of discrimination by grouping them together in clinical category A.(5,6)
Despite these caveats, the groups from the CDC classification system have been treated as disease stages by a number of studies in the AIDS literature,(4,7) and a reader of the literature should interpret results using progression within these groups with caution. Using progression to Group IV as an endpoint could classify an individual with a minor opportunistic infection and a high CD4 count (Group IV) at a more advanced stage of HIV disease than an individual who is asymptomatic but has a CD4 count of 100 (Group II), whereas the latter probably has reached a more advanced stage of HIV disease and has a poorer prognosis.
Other Classifications Proposed for Staging
Several attempts have been made at staging HIV infection using other clinical or immunologic measures in addition to the CD4 count. One of the most frequently cited in the earlier HIV literature is the Walter Reed staging classification proposed by the U.S. Army.(8) This system uses a CD4 lymphocyte count above or below 400/mm3 and the presence or absence of oral candidiasis, chronic lymphadenopathy, and delayed hypersensitivity skin test reaction. The major difficulty with this system is that a large percentage of those with HIV infection cannot be placed in a stage, and an individual can move in either direction through the stages.(9) Other more simplified staging systems have been proposed. Zolla-Pazner et al.(10) proposed an immunologic staging system using the CD4 lymphocyte count, the CD4 to CD8 ratio, and the total lymphocyte count. Royce et al.(9) reported that a four-stage scheme using only CD4 counts above and below 400/mm3 and the presence of either oral candidiasis or hairy leukoplakia performed better when applied to a cohort of HIV-positive homosexual men than either the Walter Reed or the Zolla-Pazner staging classifications. A variant on this approach by Rabeneck et al. added night sweats to the CD4 lymphocyte count and oral candidiasis.(11) None of these staging schemes has been widely adopted and each has drawbacks.
The recent availability of sensitive assays to detect and quantify the level of HIV circulating in peripheral blood (discussed in other chapters in this volume) may provide a measure that will significantly improve the ability to stage HIV disease. The level of HIV detectable in the peripheral blood is a strong predictor of the probability of developing AIDS among asymptomatic individuals (see Chapter 1.4). Earlier studies had shown that a positive test for HIV p24 antigen or elevated titers of anti**** to HIV p24 are prognostic for developing AIDS, and that other laboratory assays for products of immune activation, notably serum levels of beta2-microglobulin (B2M) and serum or urine levels of neopterin, are also strong prognostic markers independent of the CD4 lymphocyte count.(12-19) When combined with the CD4 lymphocyte count, use of these tests identified categories of significantly different risk of developing AIDS among persons with asymptomatic HIV infection, but these results have not been formalized as a staging system. The combination of CD4 lymphocyte count, quantity of HIV detected in the peripheral blood, and clinical symptoms are likely to provide the basis for future attempts at staging HIV disease.
WHO Staging System for Developing Countries
The CD4 lymphocyte count is central to the 1993 CDC classification system for HIV disease and to all of the staging systems proposed in developing countries. Counting subsets of lymphocytes, however, is often not possible in developing countries because the required technology may not be available or may be too expensive for routine use if it is available. The Global Programme on AIDS of the World Health Organization (WHO) has proposed a simplified staging system that is clinically ****d and flexible enough to be used in different parts of the world.(20) The system is ****d on four groups of clinical conditions that are considered to have prognostic significance and therefore constitute stages, plus an assessment of physical activity performance expressed as a four-point score. Patients are classified according to the highest stage recorded for either clinical condition or physical activity (Table 3).
The WHO clinical staging system was evaluated in a cross-sectional study from 20 countries that compared the clinical stages with 9 laboratory tests: CD4 lymphocyte count, total lymphocyte count, hemoglobin, hematocrit, serum beta2-microglobulin, erythrocyte sedimentation rate, HIV p24 antigen, HIV p24 anti****, and delayed-type hypersensitivity skin test.(20) They found significant differences between stages 3 and 4 for 7 out of the 9 laboratory tests, and between stages 2 and 3 for 6 out of 9 tests, but no differences between stages 1 and 2 on any laboratory test. The geometric mean values of the CD4 lymphocyte count were significantly different for stages 2, 3, and 4, but geometric mean values of the lymphocyte count alone (more readily available in developing countries) were only significantly different between stages 3 and 4. It appears that the WHO system does achieve some significant separation of prognosis by clinical staging but that the four stages can probably be collapsed into three stages with little loss of discrimination.
Lifson et al. proposed and tested a modification of the WHO system that requires the erythrocyte sedimentation rate in additional to clinical staging.(21) Although they reported "strong prognostic significance" for the stages defined by symptoms and erythrocyte sedimentation rate, their system has some of the same weaknesses as those discussed above for the CDC system as well as the additional weakness of using a laboratory measure that tends to reflect HIV-related immunosuppression but is less specific to the cellular immune deficiency than the CD4 lymphocyte count.
Surveillance of AIDS and HIV Infection
Surveillance of AIDS and HIV infection began with the recommendation by the CDC of an AIDS case definition published in Morbidity and Mortality Weekly Report (MMWR) in September 1982(22) and adopted throughout the United States and a number of other countries. Surveillance of AIDS began before HIV was identified and therefore did not initially use HIV test results. When an HIV anti**** test was introduced, reporting of HIV infection became a highly controversial issue, and within the United States, the individual states adopted different laws governing HIV reporting and different policies toward the type of testing made available in the state. The result is that there is no uniform national reporting of positive HIV tests in the United States. The status of HIV testing among the states as of this writing is discussed below, but the laws and practices around HIV test reporting have changed in many states during the last decade and are likely to change in the future.
The CDC AIDS Case Definition for Surveillance
The clinical manifestations of HIV-1 infection are numerous, involving multiple organ systems and both infectious and neoplastic disease processes. From the beginning of the AIDS epidemic, there was a need for a reportable case definition that was sensitive enough to monitor the epidemic but specific enough to exclude most cases that were not due to the then unknown agent. The first surveillance definition AIDS was defined as "a case of a disease at least moderately predictive of a defect in cell-mediated immunity occurring in a person with no known cause for diminished resistance to that disease."(22) This general definition of AIDS included a list of specific diseases and qualifications as well as a list of disqualifying conditions that were considered possible causes of non-AIDS-related diminished resistance. Many of the AIDS-defining diseases were known to occur infrequently in persons who were not HIV-infected, while other diseases occurring in HIV-positive persons were left out of the case definition because they are common in HIV-negative persons. The surveillance definition was therefore a compromise that has required revision over time as more information became available. It has undergone three major revisions in the past, the most significant revisions occurring in August 1987 and January 1993.
The AIDS case definition affects several competing interests. For surveillance purposes, the definition should be sensitive and specific, but it should also be consistent over time. For public health service providers, the number of AIDS cases in a region affects federal funding al********s, and the completeness of case reporting is an important consideration. And from the patient's point of view, the most important consideration is obtaining access to care and services, some of which depend on meeting the case definition, without exposure to possible negative social consequences from being identified as an AIDS case. As the history of revisions of the case definition given below show, these competing interests have not all been met equally.
Changes in the CDC AIDS Case Definition for Surveillance
After 1982, the definition underwent minor revisions.(23-26) Following identification of HIV,(27-29) a more substantive revision took place in June 1985, when additional diseases were added to the case definition and results from HIV anti**** tests and viral cultures began to be used, thereby increasing the specificity with which AIDS-related diseases could be identified.(30) Even so, the CDC has estimated that its 1985 revisions resulted in reclassification of less than 1% of previously reported cases.(30)
1987 Revision of the AIDS Case Definition
In August 1987, the CDC published a major revision of the adult case definition for surveillance, broadening the definition in three ways(31):
• Inclusion of HIV encephalopathy and HIV wasting syndrome.
• Inclusion of diagnoses made presumptively in cases with laboratory evidence for HIV infection.
• Elimination of exclusions due to other causes of immunodeficiency in cases with laboratory evidence for HIV infection.
The pediatric case definition for surveillance was broadened in two ways: (1) Inclusion of multiple or recurrent serious bacterial infections, and (2) inclusion of lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia in children under 13 years old.
Including presumptive diagnoses had the effect of proportionally increasing the number of women, injection drug users (IDUs), and African-Americans diagnosed with AIDS.(32) Still, the 1987 case revision was not adequate to capture all cases of severe HIV-related immunodeficiency in these groups, and further expansion of the epidemic in these populations after 1987 suggested that other clinical conditions should be added to the list. In a study of the medical records of 628 HIV-positive women and 7,008 HIV-positive men, including IDUs and non-IDUs, for every patient receiving treatment for an AIDS-defining illness, two additional HIV-positive patients were being treated for a serious disease that was probably HIV-related, but not on the list.(33) These non-AIDS-defining illnesses were primarily other pneumonias, bacterial sepsis, and pulmonary tuberculosis.
1993 Revision of the AIDS Case Definition
In January 1993, the CDC added a CD4 lymphocyte count below 200/mm3 in an HIV-positive person to the AIDS definition to sidestep the deficiencies of a definition ****d solely on a diagnosis list.(2) Three clinical conditions in an HIV-positive person were also added: pulmonary tuberculosis, two occurrences of bacterial pneumonia within a 12-month period, and, in women, invasive cervical cancer (Table 4).
The 1993 revision resulted in a large increase in the number of AIDS cases reported in 1993, primarily adding persons with a CD4 lymphocyte count below 200/mm3. The total reported in 1993 was 106,949 compared to 47,572 in 1992, less than half as many cases as in the previous year.(34) The diagnoses dates of these newly reported cases covered several years prior to 1993 so that the number of AIDS cases diagnosed in the years prior to 1993, particularly 1992 and 1991, also showed a significant increase in 1993. The rapid increase from the new definition was followed by an equally rapid decrease in 1994 and 1995, leaving the net effect of a substantial "blip" in the incidence of AIDS in the United States from 1992 to 1994. Figure 1 shows the rise and fall of AIDS incidence that resulted from the new definition (Figure 1).
The new definition requires only a single CD4 count below 200 and thus is biased toward early AIDS diagnosis in persons who may have a transient count below 200 but return to levels well above 200. Hoover et al.(35) showed that requiring at least two counts below 200 at different times would substantially reduce the proportion of persons without a clinical AIDS diagnosis and reduce the time to a first clinical diagnosis. They also showed that only 15 percent of homosexual men had a clinical AIDS diagnosis at the time their CD4 count first dropped below 200. The high variability of a single CD4 lymphocyte count is seen in the mean diurnal variation of 44/mm3 CD4 lymphocytes in seropositive men with a mean count of 333 reported by Malone et al.(36) when counts were taken at different times of the day. Finally, most AIDS-defining opportunistic infections tend to occur at counts below 200. For these reasons, adopting a single CD4 lymphocyte count below 200 to define AIDS has resulted in many AIDS cases being diagnosed much earlier in the course of HIV disease progression than previously. Estimates of the difference in survival time after an 1987 AIDS definition and a CD4 lymphocyte count below 200 show an approximate doubling of survival with AIDS from about 18 to 24 months to 36 to 48 months.(37) These estimates were made prior to the introduction of therapy with protease inhibitors and combinations of antiretroviral treatments, and it is too early to estimate how much the new therapies may extend survival with HIV infection and thus change the estimated increase in survival past an AIDS diagnosis.
A major impetus behind the 1993 revision of the case definition was the desire to increase access to medical services for those with advanced HIV disease who were not meeting the previous definition. It is not clear, however, how successful the new definition was in achieving this goal. For example, the Social Security Administration does not to accept the new definition as presumptive eligibility for disability benefits,(38) and although many AIDS opportunistic infections by themselves qualify an individual with HIV disease for supplemental social security benefits (provided he or she meets the financial means requirement), a CD4 count below 200 does not. Many local programs providing services to those with HIV disease require an AIDS diagnosis as eligibility and access to such programs may have increased as a result of the new definition. In San Francisco, however, the expected greater burden on services that was anticipated did not occur (personal communication, San Francisco Department of Public Health). The change may have had a greater effect in other ********s, but one of the most significant federal programs for those with HIV infection, the AIDS drug assistance program, which subsidizes the costs of therapies, has changed its requirements to a diagnosis of HIV infection, so an AIDS diagnosis is not required to be eligible for benefits.
Other Surveillance Definitions for AIDS Cases
The 1993 change in the AIDS case definition may have increased the number of HIV-infected persons with access to medical care, but it has made interpretation of the numbers of reported AIDS cases for epidemiologic purposes difficult. Although the CDC case definition has been used by the European countries, they did not adopt the 1993 addition to the definition of a CD4 lymphocyte count below 200 because access to services has not been a significant a problem for HIV-positive persons in most European countries, and the value for surveillance of retaining the definition ****d on diagnosed conditions was felt to be more important.(39)
WHO AIDS Surveillance Case Definition
As with the CDC classification system for HIV disease, the CDC AIDS case definition is difficult to implement in developing countries because HIV testing and the facilities for diagnosing indicator conditions are often not available. The WHO proposed a simplified AIDS surveillance case definition that would be applicable in conditions with only simple facilities available (Table 5).(39)
AIDS in an adult is defined by at least two major signs and one minor sign in the absence of known causes of immunosuppression. Generalized Kaposi's sarcoma or cryptococcal meningitis alone give a diagnosis of AIDS.
The definition has been widely used in Africa for surveillance. Evaluation of the definition has been limited by the lack of more definitive diagnoses of HIV disease for comparison, but it lacks specificity and in particular has low sensitivity. An autopsy study of patients in Abidjan found only 40 percent of those who had CDC-defined AIDS on pathologic findings had met the WHO definition.(39)
A more recent version of a case definition for AIDS in Africa that adds HIV serology and tuberculosis was proposed at a WHO workshop in Abidjan, Cote d'Ivoire in 1992 (Table 6).(40) By including HIV serology, which is increasingly available in Africa, this definition appears to have greater specificity and sensitivity than the earlier WHO definition, but it still lacks sensitivity as only about half of the autopsy cases mentioned above were classified as AIDS cases using this definition.
In addition to the simplified definitions proposed for use in Africa, the Pan American Health Organization has proposed a definition for use in Latin America, known as the Caracas definition (Table 7).(39)
Effectiveness of AIDS Surveillance
Surveillance of AIDS cases in the United States, Europe, and other developed countries has been fairly complete and has provided data useful in monitoring the epidemic and making projections. Studies of the completeness of AIDS surveillance in the United States by comparing AIDS case reports with AIDS and AIDS conditions as a cause of death on death certificates have found that reporting is better than 80 percent complete, and in several of the states studied, was 95 percent complete or higher.(41) Surveillance in other parts of the world has been much less complete, in part because of the problems in finding a simplified but specific and sensitive case definition and in part because of political resistance in some countries to acknowledging the scope of the epidemic. Although surveillance of AIDS cases has been quite good in the United States, the addition of the CD4 lymphocyte count to the case definition has made interpretation of trends difficult. In the future, surveillance of HIV-related deaths could be more epidemiologically useful than surveillance of diagnoses by providing an unchanging indicator of the epidemic if reporting of HIV-related deaths were pursued as vigorously as AIDS case reporting is currently.
HIV Test Reporting in the United States
Unlike reporting of AIDS cases by **** to state health departments, which has not been particularly controversial, reporting persons with tests positive for HIV infection to public health officials has been quite controversial. Nearly all states receive reports of AIDS by **** from county or regional health departments, but national reporting to the CDC is not by **** but by Soundex code of the last **** (a code using the first letter of the last **** and 3 numbers to represent consonants. The Soundex code does not uniquely identify a given last ****). Reports of positive HIV tests are governed by different laws in different states. In 1996, 26 states had laws requiring adults with positive HIV tests to be reported by ****; five more reported only juveniles by ****; and the remaining 19 did not report test results or reported them anonymously accompanied only by a few demographic characteristics (HIV/AIDS Surveillance Branch, CDC, personal communication). Two of the 19 states, Texas and Maryland, adopted laws in 1994 requiring positive HIV tests to be reported by a unique identifier composed of the last four digits of the social security number, birthdate, and codes for sex and race/ethnicity. This approach is a compromise between no reporting and reporting by ****, but it remains to be seen whether it is a viable alternative to ****d reporting.
The controversy over reporting HIV-positive test results opposes the arguments that ****d reporting is useful for surveillance of the epidemic in allowing unduplication of test reports, beneficial to the public health in permitting notification of at risk partners, and useful for the individual in allowing public health services to help infected persons get into earlier treatment against the arguments that ****d reporting results in fewer HIV-positive persons being tested because of confidentiality concerns and increases the possibility of breaches in confidentiality and the negative social consequences of being identified as HIV positive. There is very little convincing data to support either side of this argument as the outcomes are difficult to measure, and most research has consisted of either self-reports from at-risk individuals about how they think a particular policy would affect their test behavior or reports on the number of HIV tests following a change in the law.(42,43) Neither of these types of data addresses the more important outcomes that are said to be affected by reporting laws.
The surveillance of HIV infection is even more complex than the variation in state laws suggests because all but 9 of the 26 states with laws requiring reporting of HIV-positive individuals by **** also permit HIV testing and counseling sites that offer anonymous testing. Consequently, reporting of HIV infection does not provide complete or interpretable data on HIV test results even in most states with ****d reporting of positive HIV test results. The states with the largest numbers of AIDS cases--New York, California, Florida, New Jersey, Texas, and Illinois--had been among the states that do not report positive HIV tests, but recently New Jersey (1992) and Florida (1996) adopted ****d HIV reporting, California is considering it, and Texas adopted reporting by unique ID number (1994). These changes may reflect a tipping of the balance away from protecting patient confidentiality and toward reporting. The promise of potent antiretroviral combination therapy as effective anti-HIV treatments may tip the balance further in the direction of encouraging ****d reporting if such therapy proves to provide effective and durable early treatment of HIV infection and thereby strengthen the rationale for early detection of HIV infection. It remains to be demonstrated, however, that ****d reporting of positive HIV tests increases the number of persons getting into earlier treatment for HIV infection.
The CDC Classification Scheme for HIV Disease
The CDC classification of HIV disease was first put forth as a categorization of HIV-related symptoms into four groups and was explicitly for "public health purposes" and not "intended as a staging system,"(1) although it was frequently treated as if it were a staging system in the AIDS literature. The current CDC classification system, from the revision in 1993, combines three categories of the CD4 count with three symptom categories and is closer to a staging system but is still not described as such.(2) The CDC, however, proposed that it be used to "guide clinical and therapeutic actions in the management of HIV-infected adolescents and adults."(2) This de******ion of its intended use is close to the use of a staging system. The categories are shown in Table 1.
The definitions of the three CD4+ T-lymphocyte categories and the three categories of clinical conditions used in Table 1 follow:
• Category 1: > 500 cells/mm3 (or CD4% > 28%)
• Category 2: 200-499 cells/mm3 (or CD4% 14% - 28%)
• Category 3: < 200 cells/mm3 (or CD4% < 14%)
These categories correspond to CD4+ T-lymphocyte counts per microliter of blood. The percentage of CD4+ T cells can be substituted for the count as indicated in parentheses. The lowest accurate, but not necessarily the most recent, CD4+ T-lymphocyte count or percentage should be used for classification purposes. The percentages were derived from correlating counts and percentages from 7 data sources. The correspondence of a 200 count to 14 percent showed little variation (range from the 7 data sources: 13 to 14%), but the correspondence of a 500 count to 29 percent was more variable (range from the 7 data sources: 22.5 to 39%).(2)
Category A
Category A consists of one or more of the conditions listed below in an adolescent or adult (> 13 years) with ********ed HIV infection. Conditions listed in Categories B and C must not have occurred.
• Asymptomatic HIV infection
• Persistent generalized lymphadenopathy
• Acute (primary) HIV infection with accompanying illness or history of acute HIV infection
Category B
Category B consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical Category C and that meet at least one of the following criteria: (a) the conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or (b) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples of conditions in clinical category B include but are not limited to:
• Bacillary angiomatosis
• Candidiasis, oropharyngeal (thrush)
• Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy
• Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
• Constitutional symptoms, such as fever (38.5 degrees centigrade) or diarrhea lasting greater than 1 month
• Hairy leukoplakia, oral
• Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome
• Idiopathic thrombocytopenic purpura
• Listeriosis
• Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess
• Peripheral neuropathy
For classification purposes, Category B conditions take precedence over those in Category A. For example, someone previously treated for oral or persistent vaginal candidiasis (and who has not developed a Category C disease) but who is now asymptomatic should be classified in Category B.
Category C
Category C includes the clinical conditions listed in the 1993 AIDS surveillance case definition (see subsequent section) For classification purposes, once a Category C condition has occurred, the person will remain in Category C.
CD4 lymphocyte count or the CD4 lymphocyte percentage is generally acknowledged to follow closely the progression of HIV immunosuppression, and the CD4 lymphocyte count is currently the principal laboratory test used in clinical management of HIV infection. Recommendations for both antiviral therapy and prophylaxis of opportunistic infections are ****d on CD4 lymphocyte count or percent. Frequent AIDS diagnoses, such as PCP, are uncommon at CD4 counts above 200/mm3,(3) and other AIDS-defining conditions, such as toxoplasmosis and non-Hodgkin's lymphoma, typically occur at even lower CD4 counts. The CDC 1993 revision of the classification of HIV disease makes the three levels of CD4 lymphocyte count (0-199, 200-499, 500 and greater) central. The choice of those categories was strongly influenced by treatment recommendations at the time of the revision in 1993 to initiate antiretroviral therapy when the CD4 count fell below 500 and to initiate PCP prophylaxis when the count fell below 200. The choice of a CD4 count at 500 as one of the classifying strata is in part an artifact of strata chosen for clinical trials of antiretroviral treatments in the United States and has not been followed by some trials outside the United States that have used a stratum below 400 per microliter.(4) Many of the staging systems discussed below have used a stratification at 400 cells.
Although the 1993 classification system provides a better categorization of HIV disease than the 1986 system by groups that have generally increasing immunosuppression, its inadequacy as a staging system can be seen in the lack of a clear progression of disease severity for each of the nine categories. An individual in group A3 has AIDS by the current CDC surveillance definition even though asymptomatic and probably has a poorer prognosis than an individual in group B1 with oral candidiasis and a CD4 count of 500 per microliter. Although individuals in group A1 probably have the best prognosis in general and those in group C3, the worst, the other groups are less clearly distinguished by disease severity and prognosis.
Because the 1986 CDC HIV classification was used frequently in the AIDS literature and many studies used the 1986 Group IV disease as a clinical outcome variable, the 1986 classification scheme is shown in Table 2.(1)
The 1986 classification system as a staging system had problems similar to the 1993 revision, but it allowed for much greater inconsistency in the categories considered as disease stages because CD4 lymphocyte count was not used and persistent generalized lymphadenopathy was given a separate category (Group III). Natural history studies have failed to distinguish persons with persistent generalized lymphadenopathy from asymptomatic persons by their risk of AIDS or their CD4 lymphocyte counts and the 1993 classification system acknowledges this lack of discrimination by grouping them together in clinical category A.(5,6)
Despite these caveats, the groups from the CDC classification system have been treated as disease stages by a number of studies in the AIDS literature,(4,7) and a reader of the literature should interpret results using progression within these groups with caution. Using progression to Group IV as an endpoint could classify an individual with a minor opportunistic infection and a high CD4 count (Group IV) at a more advanced stage of HIV disease than an individual who is asymptomatic but has a CD4 count of 100 (Group II), whereas the latter probably has reached a more advanced stage of HIV disease and has a poorer prognosis.
Other Classifications Proposed for Staging
Several attempts have been made at staging HIV infection using other clinical or immunologic measures in addition to the CD4 count. One of the most frequently cited in the earlier HIV literature is the Walter Reed staging classification proposed by the U.S. Army.(8) This system uses a CD4 lymphocyte count above or below 400/mm3 and the presence or absence of oral candidiasis, chronic lymphadenopathy, and delayed hypersensitivity skin test reaction. The major difficulty with this system is that a large percentage of those with HIV infection cannot be placed in a stage, and an individual can move in either direction through the stages.(9) Other more simplified staging systems have been proposed. Zolla-Pazner et al.(10) proposed an immunologic staging system using the CD4 lymphocyte count, the CD4 to CD8 ratio, and the total lymphocyte count. Royce et al.(9) reported that a four-stage scheme using only CD4 counts above and below 400/mm3 and the presence of either oral candidiasis or hairy leukoplakia performed better when applied to a cohort of HIV-positive homosexual men than either the Walter Reed or the Zolla-Pazner staging classifications. A variant on this approach by Rabeneck et al. added night sweats to the CD4 lymphocyte count and oral candidiasis.(11) None of these staging schemes has been widely adopted and each has drawbacks.
The recent availability of sensitive assays to detect and quantify the level of HIV circulating in peripheral blood (discussed in other chapters in this volume) may provide a measure that will significantly improve the ability to stage HIV disease. The level of HIV detectable in the peripheral blood is a strong predictor of the probability of developing AIDS among asymptomatic individuals (see Chapter 1.4). Earlier studies had shown that a positive test for HIV p24 antigen or elevated titers of anti**** to HIV p24 are prognostic for developing AIDS, and that other laboratory assays for products of immune activation, notably serum levels of beta2-microglobulin (B2M) and serum or urine levels of neopterin, are also strong prognostic markers independent of the CD4 lymphocyte count.(12-19) When combined with the CD4 lymphocyte count, use of these tests identified categories of significantly different risk of developing AIDS among persons with asymptomatic HIV infection, but these results have not been formalized as a staging system. The combination of CD4 lymphocyte count, quantity of HIV detected in the peripheral blood, and clinical symptoms are likely to provide the basis for future attempts at staging HIV disease.
WHO Staging System for Developing Countries
The CD4 lymphocyte count is central to the 1993 CDC classification system for HIV disease and to all of the staging systems proposed in developing countries. Counting subsets of lymphocytes, however, is often not possible in developing countries because the required technology may not be available or may be too expensive for routine use if it is available. The Global Programme on AIDS of the World Health Organization (WHO) has proposed a simplified staging system that is clinically ****d and flexible enough to be used in different parts of the world.(20) The system is ****d on four groups of clinical conditions that are considered to have prognostic significance and therefore constitute stages, plus an assessment of physical activity performance expressed as a four-point score. Patients are classified according to the highest stage recorded for either clinical condition or physical activity (Table 3).
The WHO clinical staging system was evaluated in a cross-sectional study from 20 countries that compared the clinical stages with 9 laboratory tests: CD4 lymphocyte count, total lymphocyte count, hemoglobin, hematocrit, serum beta2-microglobulin, erythrocyte sedimentation rate, HIV p24 antigen, HIV p24 anti****, and delayed-type hypersensitivity skin test.(20) They found significant differences between stages 3 and 4 for 7 out of the 9 laboratory tests, and between stages 2 and 3 for 6 out of 9 tests, but no differences between stages 1 and 2 on any laboratory test. The geometric mean values of the CD4 lymphocyte count were significantly different for stages 2, 3, and 4, but geometric mean values of the lymphocyte count alone (more readily available in developing countries) were only significantly different between stages 3 and 4. It appears that the WHO system does achieve some significant separation of prognosis by clinical staging but that the four stages can probably be collapsed into three stages with little loss of discrimination.
Lifson et al. proposed and tested a modification of the WHO system that requires the erythrocyte sedimentation rate in additional to clinical staging.(21) Although they reported "strong prognostic significance" for the stages defined by symptoms and erythrocyte sedimentation rate, their system has some of the same weaknesses as those discussed above for the CDC system as well as the additional weakness of using a laboratory measure that tends to reflect HIV-related immunosuppression but is less specific to the cellular immune deficiency than the CD4 lymphocyte count.
Surveillance of AIDS and HIV Infection
Surveillance of AIDS and HIV infection began with the recommendation by the CDC of an AIDS case definition published in Morbidity and Mortality Weekly Report (MMWR) in September 1982(22) and adopted throughout the United States and a number of other countries. Surveillance of AIDS began before HIV was identified and therefore did not initially use HIV test results. When an HIV anti**** test was introduced, reporting of HIV infection became a highly controversial issue, and within the United States, the individual states adopted different laws governing HIV reporting and different policies toward the type of testing made available in the state. The result is that there is no uniform national reporting of positive HIV tests in the United States. The status of HIV testing among the states as of this writing is discussed below, but the laws and practices around HIV test reporting have changed in many states during the last decade and are likely to change in the future.
The CDC AIDS Case Definition for Surveillance
The clinical manifestations of HIV-1 infection are numerous, involving multiple organ systems and both infectious and neoplastic disease processes. From the beginning of the AIDS epidemic, there was a need for a reportable case definition that was sensitive enough to monitor the epidemic but specific enough to exclude most cases that were not due to the then unknown agent. The first surveillance definition AIDS was defined as "a case of a disease at least moderately predictive of a defect in cell-mediated immunity occurring in a person with no known cause for diminished resistance to that disease."(22) This general definition of AIDS included a list of specific diseases and qualifications as well as a list of disqualifying conditions that were considered possible causes of non-AIDS-related diminished resistance. Many of the AIDS-defining diseases were known to occur infrequently in persons who were not HIV-infected, while other diseases occurring in HIV-positive persons were left out of the case definition because they are common in HIV-negative persons. The surveillance definition was therefore a compromise that has required revision over time as more information became available. It has undergone three major revisions in the past, the most significant revisions occurring in August 1987 and January 1993.
The AIDS case definition affects several competing interests. For surveillance purposes, the definition should be sensitive and specific, but it should also be consistent over time. For public health service providers, the number of AIDS cases in a region affects federal funding al********s, and the completeness of case reporting is an important consideration. And from the patient's point of view, the most important consideration is obtaining access to care and services, some of which depend on meeting the case definition, without exposure to possible negative social consequences from being identified as an AIDS case. As the history of revisions of the case definition given below show, these competing interests have not all been met equally.
Changes in the CDC AIDS Case Definition for Surveillance
After 1982, the definition underwent minor revisions.(23-26) Following identification of HIV,(27-29) a more substantive revision took place in June 1985, when additional diseases were added to the case definition and results from HIV anti**** tests and viral cultures began to be used, thereby increasing the specificity with which AIDS-related diseases could be identified.(30) Even so, the CDC has estimated that its 1985 revisions resulted in reclassification of less than 1% of previously reported cases.(30)
1987 Revision of the AIDS Case Definition
In August 1987, the CDC published a major revision of the adult case definition for surveillance, broadening the definition in three ways(31):
• Inclusion of HIV encephalopathy and HIV wasting syndrome.
• Inclusion of diagnoses made presumptively in cases with laboratory evidence for HIV infection.
• Elimination of exclusions due to other causes of immunodeficiency in cases with laboratory evidence for HIV infection.
The pediatric case definition for surveillance was broadened in two ways: (1) Inclusion of multiple or recurrent serious bacterial infections, and (2) inclusion of lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia in children under 13 years old.
Including presumptive diagnoses had the effect of proportionally increasing the number of women, injection drug users (IDUs), and African-Americans diagnosed with AIDS.(32) Still, the 1987 case revision was not adequate to capture all cases of severe HIV-related immunodeficiency in these groups, and further expansion of the epidemic in these populations after 1987 suggested that other clinical conditions should be added to the list. In a study of the medical records of 628 HIV-positive women and 7,008 HIV-positive men, including IDUs and non-IDUs, for every patient receiving treatment for an AIDS-defining illness, two additional HIV-positive patients were being treated for a serious disease that was probably HIV-related, but not on the list.(33) These non-AIDS-defining illnesses were primarily other pneumonias, bacterial sepsis, and pulmonary tuberculosis.
1993 Revision of the AIDS Case Definition
In January 1993, the CDC added a CD4 lymphocyte count below 200/mm3 in an HIV-positive person to the AIDS definition to sidestep the deficiencies of a definition ****d solely on a diagnosis list.(2) Three clinical conditions in an HIV-positive person were also added: pulmonary tuberculosis, two occurrences of bacterial pneumonia within a 12-month period, and, in women, invasive cervical cancer (Table 4).
The 1993 revision resulted in a large increase in the number of AIDS cases reported in 1993, primarily adding persons with a CD4 lymphocyte count below 200/mm3. The total reported in 1993 was 106,949 compared to 47,572 in 1992, less than half as many cases as in the previous year.(34) The diagnoses dates of these newly reported cases covered several years prior to 1993 so that the number of AIDS cases diagnosed in the years prior to 1993, particularly 1992 and 1991, also showed a significant increase in 1993. The rapid increase from the new definition was followed by an equally rapid decrease in 1994 and 1995, leaving the net effect of a substantial "blip" in the incidence of AIDS in the United States from 1992 to 1994. Figure 1 shows the rise and fall of AIDS incidence that resulted from the new definition (Figure 1).
The new definition requires only a single CD4 count below 200 and thus is biased toward early AIDS diagnosis in persons who may have a transient count below 200 but return to levels well above 200. Hoover et al.(35) showed that requiring at least two counts below 200 at different times would substantially reduce the proportion of persons without a clinical AIDS diagnosis and reduce the time to a first clinical diagnosis. They also showed that only 15 percent of homosexual men had a clinical AIDS diagnosis at the time their CD4 count first dropped below 200. The high variability of a single CD4 lymphocyte count is seen in the mean diurnal variation of 44/mm3 CD4 lymphocytes in seropositive men with a mean count of 333 reported by Malone et al.(36) when counts were taken at different times of the day. Finally, most AIDS-defining opportunistic infections tend to occur at counts below 200. For these reasons, adopting a single CD4 lymphocyte count below 200 to define AIDS has resulted in many AIDS cases being diagnosed much earlier in the course of HIV disease progression than previously. Estimates of the difference in survival time after an 1987 AIDS definition and a CD4 lymphocyte count below 200 show an approximate doubling of survival with AIDS from about 18 to 24 months to 36 to 48 months.(37) These estimates were made prior to the introduction of therapy with protease inhibitors and combinations of antiretroviral treatments, and it is too early to estimate how much the new therapies may extend survival with HIV infection and thus change the estimated increase in survival past an AIDS diagnosis.
A major impetus behind the 1993 revision of the case definition was the desire to increase access to medical services for those with advanced HIV disease who were not meeting the previous definition. It is not clear, however, how successful the new definition was in achieving this goal. For example, the Social Security Administration does not to accept the new definition as presumptive eligibility for disability benefits,(38) and although many AIDS opportunistic infections by themselves qualify an individual with HIV disease for supplemental social security benefits (provided he or she meets the financial means requirement), a CD4 count below 200 does not. Many local programs providing services to those with HIV disease require an AIDS diagnosis as eligibility and access to such programs may have increased as a result of the new definition. In San Francisco, however, the expected greater burden on services that was anticipated did not occur (personal communication, San Francisco Department of Public Health). The change may have had a greater effect in other ********s, but one of the most significant federal programs for those with HIV infection, the AIDS drug assistance program, which subsidizes the costs of therapies, has changed its requirements to a diagnosis of HIV infection, so an AIDS diagnosis is not required to be eligible for benefits.
Other Surveillance Definitions for AIDS Cases
The 1993 change in the AIDS case definition may have increased the number of HIV-infected persons with access to medical care, but it has made interpretation of the numbers of reported AIDS cases for epidemiologic purposes difficult. Although the CDC case definition has been used by the European countries, they did not adopt the 1993 addition to the definition of a CD4 lymphocyte count below 200 because access to services has not been a significant a problem for HIV-positive persons in most European countries, and the value for surveillance of retaining the definition ****d on diagnosed conditions was felt to be more important.(39)
WHO AIDS Surveillance Case Definition
As with the CDC classification system for HIV disease, the CDC AIDS case definition is difficult to implement in developing countries because HIV testing and the facilities for diagnosing indicator conditions are often not available. The WHO proposed a simplified AIDS surveillance case definition that would be applicable in conditions with only simple facilities available (Table 5).(39)
AIDS in an adult is defined by at least two major signs and one minor sign in the absence of known causes of immunosuppression. Generalized Kaposi's sarcoma or cryptococcal meningitis alone give a diagnosis of AIDS.
The definition has been widely used in Africa for surveillance. Evaluation of the definition has been limited by the lack of more definitive diagnoses of HIV disease for comparison, but it lacks specificity and in particular has low sensitivity. An autopsy study of patients in Abidjan found only 40 percent of those who had CDC-defined AIDS on pathologic findings had met the WHO definition.(39)
A more recent version of a case definition for AIDS in Africa that adds HIV serology and tuberculosis was proposed at a WHO workshop in Abidjan, Cote d'Ivoire in 1992 (Table 6).(40) By including HIV serology, which is increasingly available in Africa, this definition appears to have greater specificity and sensitivity than the earlier WHO definition, but it still lacks sensitivity as only about half of the autopsy cases mentioned above were classified as AIDS cases using this definition.
In addition to the simplified definitions proposed for use in Africa, the Pan American Health Organization has proposed a definition for use in Latin America, known as the Caracas definition (Table 7).(39)
Effectiveness of AIDS Surveillance
Surveillance of AIDS cases in the United States, Europe, and other developed countries has been fairly complete and has provided data useful in monitoring the epidemic and making projections. Studies of the completeness of AIDS surveillance in the United States by comparing AIDS case reports with AIDS and AIDS conditions as a cause of death on death certificates have found that reporting is better than 80 percent complete, and in several of the states studied, was 95 percent complete or higher.(41) Surveillance in other parts of the world has been much less complete, in part because of the problems in finding a simplified but specific and sensitive case definition and in part because of political resistance in some countries to acknowledging the scope of the epidemic. Although surveillance of AIDS cases has been quite good in the United States, the addition of the CD4 lymphocyte count to the case definition has made interpretation of trends difficult. In the future, surveillance of HIV-related deaths could be more epidemiologically useful than surveillance of diagnoses by providing an unchanging indicator of the epidemic if reporting of HIV-related deaths were pursued as vigorously as AIDS case reporting is currently.
HIV Test Reporting in the United States
Unlike reporting of AIDS cases by **** to state health departments, which has not been particularly controversial, reporting persons with tests positive for HIV infection to public health officials has been quite controversial. Nearly all states receive reports of AIDS by **** from county or regional health departments, but national reporting to the CDC is not by **** but by Soundex code of the last **** (a code using the first letter of the last **** and 3 numbers to represent consonants. The Soundex code does not uniquely identify a given last ****). Reports of positive HIV tests are governed by different laws in different states. In 1996, 26 states had laws requiring adults with positive HIV tests to be reported by ****; five more reported only juveniles by ****; and the remaining 19 did not report test results or reported them anonymously accompanied only by a few demographic characteristics (HIV/AIDS Surveillance Branch, CDC, personal communication). Two of the 19 states, Texas and Maryland, adopted laws in 1994 requiring positive HIV tests to be reported by a unique identifier composed of the last four digits of the social security number, birthdate, and codes for sex and race/ethnicity. This approach is a compromise between no reporting and reporting by ****, but it remains to be seen whether it is a viable alternative to ****d reporting.
The controversy over reporting HIV-positive test results opposes the arguments that ****d reporting is useful for surveillance of the epidemic in allowing unduplication of test reports, beneficial to the public health in permitting notification of at risk partners, and useful for the individual in allowing public health services to help infected persons get into earlier treatment against the arguments that ****d reporting results in fewer HIV-positive persons being tested because of confidentiality concerns and increases the possibility of breaches in confidentiality and the negative social consequences of being identified as HIV positive. There is very little convincing data to support either side of this argument as the outcomes are difficult to measure, and most research has consisted of either self-reports from at-risk individuals about how they think a particular policy would affect their test behavior or reports on the number of HIV tests following a change in the law.(42,43) Neither of these types of data addresses the more important outcomes that are said to be affected by reporting laws.
The surveillance of HIV infection is even more complex than the variation in state laws suggests because all but 9 of the 26 states with laws requiring reporting of HIV-positive individuals by **** also permit HIV testing and counseling sites that offer anonymous testing. Consequently, reporting of HIV infection does not provide complete or interpretable data on HIV test results even in most states with ****d reporting of positive HIV test results. The states with the largest numbers of AIDS cases--New York, California, Florida, New Jersey, Texas, and Illinois--had been among the states that do not report positive HIV tests, but recently New Jersey (1992) and Florida (1996) adopted ****d HIV reporting, California is considering it, and Texas adopted reporting by unique ID number (1994). These changes may reflect a tipping of the balance away from protecting patient confidentiality and toward reporting. The promise of potent antiretroviral combination therapy as effective anti-HIV treatments may tip the balance further in the direction of encouraging ****d reporting if such therapy proves to provide effective and durable early treatment of HIV infection and thereby strengthen the rationale for early detection of HIV infection. It remains to be demonstrated, however, that ****d reporting of positive HIV tests increases the number of persons getting into earlier treatment for HIV infection.