The Incidence of AIDS-Defining Illnesses in 4883 Patients With Human Immunodeficiency Virus Infection FREE

A NATURAL order of acquired immunodeficiency syndrome (AIDS)–defining diseases, defined by the CD4 lymphocyte count, has been suggested in patient populations of various sizes.^1- 3 Knowledge of the risk of a specific disease according to the level of CD4 lymphocyte counts allows clinicians to screen patients for the most likely diseases, given their CD4 lymphocyte count, and to target prophylaxis at the most relevant population. It is also important to establish if the risk of a particular disease varies according to basic demographic variables, such as age or sex, or if the risk of the disease continues to increase as the CD4 lymphocyte count decreases. A study by Bacellar et al⁴ reports the incidence of opportunistic infections in patients with CD4 lymphocyte counts below 0.1×10⁹/L (100/mm³), but does not detail the incidence at very low CD4 lymphocyte counts (<0.05-0.025×10⁹/L). Trials of new agents for the prophylaxis of opportunistic infections are increasingly being undertaken. Disease prophylaxis can have a high cost and patients who need prophylaxis are those who require more intensive clinical monitoring. Therefore, it is of great importance to determine the optimal time to initiate prophylaxis and to estimate the cost and benefit obtained from such new interventions.⁵

The Royal Free and Chelsea and Westminster Hospitals in London, England, have a large patient population and have data collected for up to 10 years. During this period, comprehensive data on more than 4500 patients infected with the human immunodeficiency virus (HIV), of whom 2500 were patients with AIDS, were collected. Information on all AIDS-defining illnesses and CD4 lymphocyte counts recorded during follow-up were prospectively collected. To our knowledge, there has been no previous study that has determined the incidence of each AIDS-defining illness over a wide range of CD4 lymphocyte counts in such a large patient population. Therefore, the aim of this study was to determine the CD4 lymphocyte counts at which AIDS-defining illnesses are diagnosed in England, and to investigate the changing incidence of each of the AIDS-defining illnesses as the CD4 lymphocyte value declines.

All patients diagnosed as having HIV and with at least 1 recorded CD4 lymphocyte count from the Chelsea and Westminster Hospital (CWH) from 1982 to July 1995 or the Royal Free Hospital (RFH) from 1986 to August 1994 were included in this study. Prospective data collection began at the CWH in 1986 and at the RFH in 1990; retrospective data for all patients with HIV ever seen at the 2 sites were added at this time. Several data exercises have since confirmed the accuracy and completeness of the data. In particular, at both sites a comprehensive search ensured that all patients were added to the database, including patients who had died or who were unavailable for follow-up before prospective data collection began. Demographic data, details of all AIDS-defining illnesses, date of death, and immunological data are maintained in a separate database at each site. A diagnosis of AIDS was made according to the definition in use at the time, and patients were not retrospectively diagnosed as having AIDS. Patient follow-up varied for each AIDS-defining illness and was measured as the time between the first CD4 lymphocyte count and the development of the AIDS-defining illness of interest. Patients who did not develop the AIDS-defining illness were eliminated from the analysis at death or at the date of their last clinic visit if they did not die during the study.

In some cases, patients gave a history of an AIDS-defining illness at their first visit, and information from these illnesses was excluded from this analysis. This was because verifying the accuracy of historical diagnoses and completeness of CD4 lymphocyte counts at the time of diagnosis was mainly incomplete. For example, a patient diagnosed as having Pneumocystis carinii pneumonia as an initial AIDS-defining illness before his or her first visit to the RFH would not contribute any information to the analysis of the average CD4 lymphocyte count at diagnosis of P carinii pneumonia, or the incidence of disease in different CD4 lymphocyte count strata, even if it was diagnosed again at a later date while at the RFH. If this patient was then diagnosed as having cryptosporidiosis after 6 months of follow-up, this information would be included in the estimate of the median CD4 lymphocyte counts at which cryptosporidiosis occurs. Only the first occurrence of each AIDS-defining illness has been noted, since there are inherent difficulties in determining the end of one episode and the onset of a new, distinct episode.

All statistical analyses were performed using SAS software.⁶ The median CD4 lymphocyte count at diagnosis was calculated for each of the AIDS-defining illnesses, and was compared in different groups using nonparametric tests, such as the Kruskal-Wallis test. Patients diagnosed as having progressive multifocal leukoencephalopathy (39 patients), histoplasmosis (6 patients), isosporiasis (9 patients), and recurrent Salmonella septicemia (10 patients) were grouped together to form a single category of diagnoses. The CD4 lymphocyte count was divided into several groups: higher than 0.20×10⁹/L, 0.101-0.20×10⁹/L, 0.051-0.10×10⁹/L, 0.026-0.05×10⁹/L, and 0.025×10⁹/L or less. The incidence of each disease per 100 person-years (PY) of follow-up in each category was calculated using a PY analysis. Confidence intervals were constructed assuming a Poisson distribution of events. Follow-up in each strata begins when the patient's CD4 lymphocyte count falls in the range of the strata, and ends either with the development of an AIDS-defining illness, the death of the patient, or a decline in CD4 lymphocyte counts such that the patient moves to another strata. The incidence rate in each strata is then the number of events divided by the total PY of follow-up. Patients were not allowed to move in the reverse direction through the CD4 lymphocyte count categories; thus, the data presented are the incidence according to the minimum CD4 lymphocyte count measured.

In total, 4883 patients from the RFH (907 patients [18.6%]) and CWH (3976 patients [81.4%]) had at least 1 CD4 lymphocyte count measured during a median follow-up period of 27.6 months (90% range, 1-107.6 months), measured from the date of the first hospital visit. Measurement of the CD4 lymphocyte count began in March 1983 at CWH and in February 1982 at RFH. The median number of CD4 lymphocyte count determinations during follow-up was 7 (90% range, 1-33). During follow-up, CD4 lymphocyte counts were measured more regularly at RFH; the median number of CD4 lymphocyte counts measured per year of follow-up was 7.8 at RFH and 3.4 at CWH (Wilcoxon P<.001). Table 1 describes the patients included in this study. The majority of the patients were male (4513 [92.5]) and belonged to the homosexual or bisexual exposure category (3959 [81.1]). The median age at diagnosis of HIV was 31.9 years (90% range, 22.1-49.9 years), while the median year of HIV diagnosis was 1990. The median CD4 lymphocyte count within 6 months of the initial visit was 0.27×10⁹/L (90% range, 0.01-0.76×10⁹/L), and this information was available for 3517 patients (72.0%).

During the follow-up period, a total of 3875 incident AIDS-defining illnesses were diagnosed in 1713 patients. Figure 1 describes the AIDS-defining illnesses diagnosed in this group, together with the distribution of CD4 lymphocyte counts at diagnosis. This illustration is ordered according to the median CD4 lymphocyte count at diagnosis. The 5 most common AIDS-defining illnesses were, in decreasing order, P carinii pneumonia (649 patients [16.7%]), esophageal candidiasis (589 patients [15.2%]), Kaposi sarcoma (510 patients [13.2%]), Mycobacterium avium–intracellulare complex (372 patients [9.6%]), and cytomegalovirus retinitis (367 patients [9.5%]). The median CD4 lymphocyte count at diagnosis ranged from 0.011×10⁹/L in patients diagnosed as having cytomegalovirus retinitis to 0.102×10⁹/L in patients diagnosed as having extrapulmonary tuberculosis.

Figure 2 summarizes the incidence of each of the AIDS-defining illnesses, ordered from the most common diagnosis to the least. The incidence is expressed per 100 PY of follow-up. Patients who died were eliminated from analysis at the date of death; all other patients were eliminated from analysis at their last clinic visit. With the exception of pulmonary tuberculosis and recurrent pneumonia, diagnoses added to the 1992 revision of the Centers for Disease Control and Prevention surveillance definition for AIDS, the total duration of follow-up exceeds 10000 PY of follow-up. The overall incidence ranges from 6.22 per 100 PY (95% confidence interval, 5.74-6.70) for P carinii pneumonia to 0.37 per 100 PY for extrapulmonary tuberculosis (95% confidence interval, 0.26-0.48). Table 2 presents the incidence of each AIDS-defining illness according to CD4 lymphocyte count. Generally speaking, the incidence of each AIDS-defining illness continued to increase as the CD4 lymphocyte count declined. Diseases such as cytomegalovirus and mycobacterial disease, which are less common as initial AIDS-defining illnesses, had a very low incidence until the CD4 lymphocyte count declined to below 0.05×10⁹/L, while diseases such as Kaposi sarcoma, P carinii pneumonia, and esophageal candidiasis had a higher incidence at higher CD4 lymphocyte counts.

There were some differences in the incidence of disease according to sex and exposure category, as shown in Table 3. This table has not been further divided according to CD4 lymphocyte count strata because the number of events in individual strata rapidly becomes very small. As expected, the incidence of Kaposi sarcoma was much higher in men compared with women (incidence, 4.96 and 0.91, respectively) and in homosexual men compared with all other exposure categories combined (incidence, 5.13 and 2.23, respectively). It is possible that patients included in the "unknown" exposure category were actually homosexual or bisexual men; this may explain the relatively high incidence of Kaposi sarcoma in the combination of other exposure groups. The incidence of esophageal candidiasis was also considerably higher among male patients compared with female patients (incidence, 5.53 and 2.64, respectively).

There were also some differences in the incidence of AIDS-defining illnesses according to year of HIV diagnosis, as shown in Table 4 and Table 5. Table 4 presents the changing incidence of M avium–intracellulare complex. The CD4 lymphocyte categories higher than 0.05×10⁹/L have been combined due to the small number of events, as have years after 1992. There is a clear increase in the incidence of M avium–intracellulare complex in patients diagnosed as having HIV after 1992 at lower CD4 lymphocyte counts, but at higher CD4 lymphocyte counts the incidence remained consistently low. Table 5 presents similar figures for P carinii pneumonia, and here the CD4 lymphocyte count categories lower than 0.05×10⁹/L have been combined. After 1988, the incidence of P carinii pneumonia steadily decreased in the higher CD4 lymphocyte count categories, while at lower CD4 lymphocyte counts the incidence increased slightly.

It is clear that there are considerable differences in the CD4 lymphocyte count at which different AIDS-defining illnesses occur. Previous studies have described the distribution of CD4 lymphocyte counts according to AIDS-defining illnesses,^1- 3,7 but these studies tend to be of much smaller numbers of patients, which means that the average CD4 lymphocyte count at which some of the less common diseases occurs could not be estimated. The order of disease occurrence in this study was consistent with those of other studies. This order ranges from diseases such as lymphomas and tuberculosis, which typically occur at higher CD4 lymphocyte counts,^1,7- 9 to diseases such as M avium–intracellulare complex^1,10- 13 and cytomegalovirus disease,^7,12,14- 15 which are infrequently observed in patients with CD4 lymphocyte counts higher than 0.05×10⁹/L.

This study reflects the incidence of AIDS-defining illnesses in a large population of HIV-positive patients. A study of patients with AIDS would find a higher overall incidence of disease than that reported here; in contrast, a study of seroconverted patients would report a much lower overall incidence than reported here. This makes comparisons with other studies difficult, since few studies have reported the incidence of AIDS-defining diseases according to CD4 lymphocyte strata. Moore and Chaisson³ report a higher incidence of disease than that found in this study, but this may be due to differences in study design and the duration of patient follow-up. In other studies, the incidence of disease has often been quoted as a proportion of patients who develop disease within 1 or 2 years of the CD4 lymphocyte count dropping below some arbitrary level.^16- 18 Those studies that address the increasing incidence of disease as CD4 lymphocyte counts decrease report similar findings to this study, that is, that the incidence of disease increases as CD4 lymphocyte counts decrease,^19- 20 although the categories of CD4 lymphocyte counts used in other studies are much wider than those used here. This study is unique in the number of patients included, the number of incident AIDS-defining illnesses, and its use of follow-up CD4 lymphocyte counts, which enable the occurrence of a disease to be related to the CD4 lymphocyte count at which it occurs more accurately.

The incidence of all AIDS-defining illnesses was highly dependent on the CD4 lymphocyte count. This information may prove to be extremely useful in the development of prophylaxis and screening tests. For example, the incidence of cytomegalovirus retinitis in patients with a CD4 lymphocyte count higher than 0.025×10⁹/L was low, hence prophylaxis may only be appropriate in patients with very low CD4 lymphocyte counts. Similarly, if a patient presented with symptoms suggestive of cytomegalovirus retinitis, measurement of the CD4 lymphocyte count may provide some indication of how likely the diagnosis is. The optimal time to initiate prophylaxis is a complex issue; prophylaxis is necessary when the disease is common, but the best improvement in outcome may be by preventing the disease at earlier CD4 lymphocyte counts. For the majority of the diseases, the incidence increased as the CD4 lymphocyte count declined. Late-stage diseases, such as cytomegalovirus retinitis and M avium–intracellulare complex, had a very low incidence before the CD4 lymphocyte count dropped below 0.025×10⁹/L. However, it should be noted that at CD4 lymphocyte counts between0.025 and 0.05×10⁹/L, the incidence of, for example, cytomegalovirus was higher than the incidence of P carinii pneumonia at CD4 lymphocyte counts between 0.10 and 0.20×10⁹/L. In contrast, diseases such as Kaposi sarcoma and esophageal candidiasis had a relatively high incidence throughout all CD4 lymphocyte count categories.

GUIDELINES FROM the Centers for Disease Control and Prevention for the prophylaxis of opportunistic infections suggest that prophylaxis against P carinii pneumonia should begin at CD4 lymphocyte counts of 0.20×10⁹/L, against toxoplasmosis at 0.10×10⁹/L, and against M avium–intracellulare complex at 0.075×10⁹/L.²¹ In this study, the incidence of P carinii pneumonia among all patients with a CD4 lymphocyte count below 0.20×10⁹/L was 13.5 per 100 PY of follow-up, while the incidence of toxoplasmosis at CD4 lymphocyte counts below 0.10×10⁹/L was much lower (3.33). At CD4 lymphocyte counts higher than 0.05×10⁹/L, the overall incidence of both cytomegalovirus disease or M avium–intracellulare complex was very low (0.49 and 0.58 per 100 PY of follow-up, respectively), which may suggest that a CD4 lymphocyte count of 0.05×10⁹/L may be the most appropriate time to start prophylaxis for these infections.

In this study, female patients were at a significantly reduced risk of esophageal candidiasis compared with males. This contrasts with previous reports, in which esophageal candidiasis has been reported more commonly in females.^22- 25 The higher frequency reported in females previously has been attributed to the frequency of vaginal candidiasis observed in women infected with HIV.²⁴ There was also a reduced risk of Kaposi sarcoma in all exposure groups compared with homosexual men. Kaposi sarcoma has been reported to be up to 10 times more common in homosexual men,^17,26 and it has been reported in most other exposure groups to a certain extent.²⁷ A woman's risk of developing Kaposi sarcoma may be closely associated with her partner's exposure category.²⁷ Various studies now provide evidence that a newly identified human herpesvirus may be the cause of Kaposi sarcoma,^28- 30 and this may help to explain the high risk of Kaposi sarcoma in homosexual men.

This study confirmed the increasing incidence of M avium–intracellulare complex in patients diagnosed as having HIV in more recent years, but found no evidence of an increase in cytomegalovirus infections.^16,31- 33 By preventing or delaying death from opportunistic infections such as P carinii pneumonia without stopping the decline in immune function, clinical manifestations more common with advanced immunosuppression become more prevalent.^4,34 In addition, improvements in diagnosing M avium–intracellulare complex infection may explain its increase in recent years. It was also interesting to note that the incidence of P carinii pneumonia at higher CD4 lymphocyte counts declined steadily since 1988, consistent with the introduction of effective prophylaxis against P carinii pneumonia.^35- 36

A potential bias of this study is that patients may not report their history of AIDS-defining illnesses accurately. If a patient had been diagnosed as having cryptosporidiosis but it was not reported at his or her first visit to RFH, that patient could be incorrectly included in an analysis of the average CD4 lymphocyte count for cryptosporidiosis at the first recurrence of this disease. If this bias was present, it would have the effect of lowering the CD4 lymphocyte counts at which each disease occurs, inflate the incidence of disease at lower CD4 lymphocyte counts, and decrease survival after a specific diagnosis. It is difficult to ascertain the extent to which patient self-reporting agrees with medical history. In some cases, patients bring documented evidence of their medical history, but this is not always the case. Previous studies in unrelated medical conditions have suggested that the accuracy of recall of medical histories depends on the diagnosis, the length of the recall period, and a potential reluctance to answer sensitive questions.^37- 39 This patient group had a median survival after an initial AIDS diagnosis of 20 months,⁴⁰ which compares favorably with other reports of survival and may suggest that this potential bias is small. In addition, since both historical events and recurrences of illnesses were excluded from the analysis, the incidence rates should be regarded as minimum estimates.

This study did not consider the relationship between prophylaxis against P carinii pneumonia, antiretroviral treatment, and the incidence of disease. An alternative method to investigate these relationships would be to use Cox proportional hazards models. The relationship between the risk of disease and specific factors, such as age, sex, exposure group, CD4 lymphocyte counts, and treatment, could be investigated in greater detail. In addition, information about HIV viral load may add to the results of this study and help to identify those patients at greatest risk of a specific AIDS-defining illness, but little information on this area is available to date.

The clinical care and disease progression of patients with HIV and AIDS has been substantially altered by the development of protease inhibitors; patients in this study had little exposure to these drugs due to the cutoff date for the analysis. Initial evidence suggests that the incidence of AIDS-defining illnesses has been dramatically reduced by the use of protease inhibitors.⁴¹ In the future it will be of great interest to compare the median CD4 lymphocyte counts at which AIDS-defining illnesses occur in patients who take protease inhibitors, and to confirm the declining incidence of opportunistic infections.

In conclusion, this study provides important information about the incidence of AIDS-defining illnesses across a wide range of CD4 lymphocyte counts, enabling disease-specific prophylaxis to be targeted at the most appropriate population. In the future, as more prophylactic therapies are developed, this study will provide important historical data on the incidence of diseases before specific prophylaxis was introduced. The cost of caring for patients with HIV will vary greatly according to the opportunistic infections that arise and how they are treated. This study provides important information about the incidence of disease, given a CD4 lymphocyte count, that can be used to guide decisions about the best time to begin prophylaxis, both in terms of cost and benefit.

Accepted for publication July 17, 1997.

Members of the Royal Free/Chelsea and Westminster Hospitals Collaborative Group include the following. At RFH: Margarita Bofill, Sanjay Bhagani, Francis Bowen, Tony Drinkwater, Angela Dykhoff, Jonathan Elford, Vince Emery, Debbie Farmer, Paul Griffiths, George Janossy, Margaret A. Johnson, Steve Jolles, Sabine Kinloch, Christine Lee, Clive Loveday, Marc Lipman, Sara Madge, Amanda Mocroft, Adeola Olaitan, Andrew Phillips, Caroline Sabin, and Mervyn Tyrer. At CWH: Simon Barton, Fiona Boag, Phillipa Easterbrook, Brian Gazzard, Ramesh Halai, David Hawkins, Adam Laurence, Julian Morcinek, Mark Nelson, and Michael Youle.

Reprints: Amanda Mocroft, PhD, HIV Research Unit, Department of Primary Care and Population Sciences, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2PF, England.