3.1 Introduction
The analyses presented in this chapter are from the AIDS in Europe Study. Survival from each of the AIDS defining diseases is considered and used to develop a ranking of diseases. The extent to which the ranking of diseases holds after stratification for potentially important confounding factors, such as the use of zidovudine, year of diagnosis and CD4 lymphocyte count is considered.
3.2 Literature Review
In clinical trials of treatment for HIV infection, the major outcome is often based on clinical endpoints such as death, or development of a further AIDS defining illness^®'®®. However, the events which constitute an endpoint may not be equally weighted, and thus vary considerably in terms of the risk of death®^. For example, a patient with a series of opportunistic events such as cryptosporidiosis followed by toxoplasmosis within a few months, may be considered to have a more favourable outcome than a patient experiencing a single, comparatively mild disease, such as oesophageal candidiasis, if this event occurred earlier during follow up.
A summary measure, utilising the natural rankings of the diseases may be appropriate and useful in clinical trials. To date, however, few studies have specifically addressed the ranking of AIDS defining diseases®®'®®. Crowe et a/®® defined the order of commonly encountered HIV-related opportunistic infections and malignancies according to the median CD4 lymphocyte count at which they occur. More recently, Luo at a/®® divided diseases into two classes; ’mild’ and ’severe’, and showed that the prognosis in each class was quite distinct. In addition, it was formally confirmed that survival in AIDS patients with more than one AIDS defining illness at initial diagnosis of AIDS was reduced compared to patients with a single diagnosis, as suggested by a number of earlier studies®®'®®-®®.
Some rankings of disease may be implied from observational studies of the natural history of patients with AIDS. There is considerable evidence that patients diagnosed with Kaposi’s sarcoma, considered to be an early AIDS diagnosis®^, have a better survival than those diagnosed with most other AIDS defining illness®®®®'®®®®'^® possibly because Kaposi’s sarcoma tends to develop at higher CD4 lymphocyte counts than other
diagnoses®^’^^. Diseases such as lymphoma have a particularly poor prognosis®® ^®'^®, as does cytomegalovirus disease®® ®^’^^’^®'^® and infection with Mycobacterium avium
complex^®'®®, the latter two of which tend to occur during the latter stages of AIDS when the CD4 lymphocyte count has fallen to 50/mm® or less®®'^^®\
Mortality after a second episode ot Pneumocystis carinii pneumonia was initially reported to be higher compared to a first episode, which may have been due to the lack of effective treatment®^"®®. More recent evidence has shown similar survival rates for first and subsequent episodes®"*. In addition to Kaposi’s sarcoma, diagnoses such as oesophageal candidiasis and extrapulmonary tuberculosis have longer median survival times^'*'^®’®®’®®, while the severity of disease resulting from an infection such as cryptosporidiosis is highly variable. Such variation may be related to the degree of immunosuppression at diagnosis®^.
3.3 Survival and Ranking of Diseases 3.3.1 Survival Following a Given Diagnosis
- The median survival after a given diagnosis of each of nineteen AIDS indicator illnesses, regardless of whether this occurred as a first AIDS defining condition or during subsequent follow-up, is shown in Table 3.1, together with the 25th and 75th percentiles. Survival after a diagnosis of either histoplasmosis or isosporiasis could not be calculated, as only 17 patients were diagnosed with each of these diseases. Diseases have been assigned a rank according to their median survival. Where diseases share a similar prognosis, they have been ranked according to the number of diagnoses made; the higher number is assigned the lowest rank.
A diagnosis of progressive multifocal leukoencephalopathy was associated with the worst median survival of just two months, extrapulmonary tuberculosis had the most favourable prognosis of 19 months. More than half of the AIDS defining illnesses had a median survival of six months or under; only three diagnoses {Pneumocystis carinii pneumonia, Kaposi’s sarcoma and extrapulmonary tuberculosis) had a median survival of over twelve months. The most commonly diagnosed AIDS defining diseases were Pneumocystis
carinii pneumonia (3293 patients), Kaposi’s sarcoma (1919 patients) and oesophageal
Table 3.1
Median survival time (months) for each AIDS defining event
Disease* N Median Survival
(25-75 percentile) Rank* Progressive multifocal leukoencephalopathy 104 2 ( 1 - 5 ) 1 Malignant lymphoma 401 3 ( 1 - 8 ) 2
AIDS dementia complex 697 4 (1 - 12) 3
Cytomegalovirus (exc. retinitis) 641 4 (0 - 12) 4
Mycobacterium avium, extrapulmonacy 401 4 (2 - 12) 5
Other mycobacterium, extrapulmonary 107 5 (1 - 11) 6
Candidiasis, pulmonary 78 5 (1 - 1 1 ) 7
Cytomegalovirus retinitis 804 6 ( 3 - 1 3 ) 8
Cryptosporidiosis 432 6 (2 - 16) 9
Cryptococcosis 308 6 (1 - 15) 10
Toxoplasmosis 1028 8 ( 3 - 1 7 ) 11
HIV wasting syndrome 463 8 (2 - 20) 12
Salmonella septicaemia 123 1 0 ( 4 - 2 0 ) 13
Herpes simplex, not skin 59 1 0 ( 2 - 2 1 ) 14
Oesophageal candidiasis 1869 1 2 ( 5 - 2 3 ) 15
Herpes simplex ulceration 367 1 2 ( 5 - 2 3 ) 16
Pneumocystis carinii pneumonia 3293 14 (5 - 25) 17
Kaposi's sarcoma 1919 1 5 ( 7 - 2 6 ) 18
Tuberculosis, extrapulmonary 695 1 9 ( 7 - 3 7 ) 19
Diseases are ranked according to median survival. In the case of similar median survival times, diseases are ranked according to number of patients
Survival for each disease is calculated regardless of whether it was the first or subsequent AIDS event.
3.3.2 Survival After an Initial Diagnosis Compared to Subsequent Diagnoses
The overall ranking of diseases, as assigned in Table 3.1, were also found to be consistent when events were stratified according to whether the diagnosis occurred as an initial AIDS defining event or during subsequent follow-up, as shown in Table 3.2.
Table 3.2
Median survival time (months) - stratification for time of AIDS event
Disease Initial event N Median Survival During foiiow-up N Median Survival Progressive multifocal leukoencephalopathy 47 2 57 2 Malignant lymphoma 228 5 173 1
AIDS dementia complex 295 8 402 3
Cytomegalovirus (exc. retinitis) 240 7 401 3
Mycobacterium avium, extrapulmonary 104 8 297 4
Other mycobacterium, extrapulmonary 40 8 67 4
Candidiasis, pulmonary 48 6 30 5
Cytomegalovirus retinitis 154 8 650 6
Cryptosporidiosis 216 8 216 5
Cryptococcosis 158 9 150 4
Toxoplasmosis 512 11 516 6
HIV wasting syndrome 328 12 135 3
Salmonella septicaemia 70 15 53 7
Herpes simplex, not skin 30 17 29 5
Oesophageal candidiasis 1212 14 657 8
Herpes simplex ulceration 199 15 168 9
Pneumocystis carinii pneumonia 2517 17 776 7
Kaposi’s sarcoma 1394 17 525 8
Diseases are ranked in the same order as found in Table 3.1. Diseases diagnosed during follow-up have a much shorter median survival time; none have a median survival of longer than 9 months. In general, when a disease was diagnosed as an initial AIDS defining event, median survival was twice as long as when the diagnosis was made during subsequent follow-up.
Figure 3.1 illustrates the frequency with which diseases were diagnosed as an initial AIDS defining event or as a subsequent event, for the seven most common diagnoses in this patient group. Those diseases with the highest ranks and the longest median survival from Table 3.1, such as Pneumocystis carinii pneumonia and Kaposi’s sarcoma, were all diagnosed much more commonly as an initial AIDS defining event (p < 0.0001, chi- squared test). In contrast, diseases with the lowest ranks, such as cytomegalovirus retinitis and AIDS dementia complex, were.all diagnosed more commonly during follow-up (p < 0.0001, chi-squared test).
Figure 3.1
Initial and subsequent AIDS defining illnesses
OC 1 2 1 2