Changes over calendar time in the risk of specific first AIDS-defining events following HIV seroconversion, adjusting for competing risks

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1 International Epidemiological Association 2002 Printed in Great Britain International Journal of Epidemiology 2002;31: Changes over calendar time in the risk of specific first AIDS-defining events following HIV seroconversion, adjusting for competing risks CASCADE Collaboration a Background Although studies have reported large reductions in the risks of AIDS and death since the introduction of potent anti-retroviral therapies, few have evaluated whether this has been similar for all AIDS-defining diseases. We wished to evaluate changes over time in the risk of specific AIDS-defining diseases, as first events, using data from individuals with known dates of HIV seroconversion. Methods Using a competing risks proportional hazards model on pooled data from 20 cohorts (CASCADE), we evaluated time from HIV seroconversion to each first AIDS-defining disease (16 groups) and to death without AIDS for four calendar periods, adjusting for exposure category, age, sex, acute infection, and stratifying by cohort. We compared results to those obtained from a cause-specific hazards model. Results Of 6941, 2021 (29%) developed AIDS and 437 (6%) died without AIDS. The risk of AIDS or death remained constant to 1996 then reduced; relative hazard = 0.89 (95% CI: ); 0.90 (95% CI: ); and 0.32 (95% CI: ) for , , and , respectively, compared to Significant risk reductions in were observed in all but two AIDSdefining groups and death without AIDS in a competing risks model (with similar results from a cause-specific model). There was significant heterogeneity in the risk reduction across events; from 96% for cryptosporidiosis, to 17% for death without AIDS (P ). Conclusion These findings suggest that studies reporting a stable trend for particular AIDS diseases over the period may not have accounted for the competing risks among other events or lack the power to detect smaller trends. Keywords Seroconverters, HIV, AIDS-defining diseases, proportional hazards model, competing-risks models Accepted 11 March 2002 To date, there is good agreement among researchers that the incubation period of AIDS, prior to the introduction of highly active anti-retroviral therapy (HAART), was strongly dependent on age at infection with a median time of 7.7 and 11 years for those aged and years, respectively. 1,2 Monitoring the temporal changes in the incubation period of AIDS continues to have important public health implications because it allows evaluation of the potential detrimental effect of the a See Appendix. Correspondence: Patrizio Pezzotti, Istituto Superiore di Sanita, Viale Regina Elena, 299, Rome, Italy. patrizio.pezzotti@iss.it Reprints: Dr Kholoud Porter, MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. kp@ctu.mrc.ac.uk circulation of different viral subtypes and of drug-resistant viruses, as well as the evaluation of the effectiveness of therapeutic strategies at a population level. 3 Such a comparison of the risk of AIDS across calendar periods ideally assesses the cumulative effect of applying current treatment policies across clinical practice. In reality some of this variation may be due to concurrent changes in patient management other than treatment policy. The introduction of combination antiretroviral therapies, especially HAART, in the mid-1990s has been associated with a reduction in morbidity and mortality of HIV-infected individuals at a population level, 4 6 which has lengthened the incubation period of HIV infection and overall survival. 7 9 However, though the risk of AIDS has fallen overall, the effect of HAART on specific AIDS-defining diseases remains unclear. 951

2 952 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Only a few studies have tried to evaluate whether the effectiveness of these therapies has been similar for all AIDSdefining opportunistic infections and malignancies using a population effectiveness approach All but one of these studies, however, were based on the follow-up of individuals with prevalent HIV infection (i.e. unknown HIV infection duration) from specific levels of CD4 cell counts rather than seroconversion, and did not take into account competing risks among the specific AIDS-defining diseases and death without an AIDS diagnosis. One seroincident study which adjusted for competing risks was only able to consider a limited number of AIDS-defining opportunistic infections. 14 The objective of this study was thus to evaluate the effect of calendar period on the risk of developing AIDS (overall) and on the risk of developing each specific AIDS-defining disease as the first AIDS-defining event or of dying without AIDS on a large data-set of individuals with known date of HIV seroconversion. We used a competing risks model in analyses to allow for the fact that an increase in the incidence of one AIDS-specific disease may simply be due to decreasing incidence of other events as more people remain at risk. We compared results with those derived from a cause-specific model. Materials and Methods Study population Data from a collaboration of 20 seroconverter cohorts in Europe and Australia (CASCADE: Concerted Action on SeroConversion to AIDS and Death in Europe 15 ) pooled in 2001 were used in the analysis. In brief, all are cohorts of HIV-1-infected individuals for whom it was possible to estimate the time of HIV seroconversion (year of first seroconversion ranged from 1979 to 1995 across the studies [median 1983]: last seroconversion from 1985 to 2000 [median 1998]). Seroconversion was estimated by various methods, the most common being the mid-point between the first positive and last negative antibody test dates with a maximum 3-year interval between test dates. 15 People aged under 15 years at seroconversion were excluded from all analyses as the definition of AIDS differs in children. Statistical analysis We investigated secular trends in time from seroconversion to specific first AIDS-defining diseases, based on the 1993 European AIDS case definition, 16 and death without AIDS through proportional hazards models. 17 A CD4 cell count 200 cells/ml with no clinical AIDS diagnosis was not considered as AIDS. The AIDS diagnoses were ascertained through clinical follow-up and through matching with AIDS registries by the original cohort investigators. Only some of the cohorts collect data on AIDSdefining diseases subsequent to the first AIDS event, so events after the first were not considered here. The AIDS-defining diseases were grouped as follows (all 30 events): candidiasis; cryptococcosis; cryptosporidiosis; cytomegalovirus (CMV) disease; HIV encephalopathy; herpes simplex disease (HSV); Kaposi s sarcoma (KS); lymphoma; Pneumocystis carinii pneumonia (PCP); progressive multifocal leucoencephalopathy (PML); recurrent pneumonia; tuberculosis (TB: pulmonary and extrapulmonary); cerebral toxoplasmosis; HIV wasting syndrome; other mycobacterial diseases not including TB (MAI). All other AIDS-defining events (invasive cervical carcinoma [n = 9], coccidioidomycosis [1], isosporiasis [4], and Salmonella septicaemia [12] and diagnosis unknown [7]) were grouped together because of the few events observed in each. The groupings were based mainly on aetiologic criteria, but were fairly broad because not all cohorts recorded AIDS events to the same level of detail (e.g. KS rather than skin KS or visceral KS). When considering an outcome such as time to AIDS or death, which has several components, there are two possible approaches to analysis to investigate the effect of factors on time to the specific events making up this endpoint. A cause-specific hazard 18,19 is the only directly estimable quantity from such data and a competing risks hazard 20 can be calculated via the cause-specific hazard: these two hazards have very different interpretations. Proportional hazards models can be specified to estimate the effect of factors on either the competing risks 20 or cause-specific 21 hazard. In both cases, only the first AIDSdefining events are considered to explore time to a specific AIDS-defining disease as progression to AIDS. The cause-specific hazard for each AIDS-defining disease (or death without a recorded AIDS diagnosis) at any timepoint, t, is the instantaneous risk of developing that disease as the first event, conditional on being alive and AIDS-free just prior to t. This conditioning means that the cause-specific hazard cannot be truly specific to the AIDS event of interest because factors which directly influence other AIDS events can have an indirect effect on the event in question. In the cause-specific model, individuals who develop a different AIDS-defining disease first are censored at this time when considering all other AIDSdefining diseases. The overall hazard of AIDS or death at any time equals the sum of the cause-specific hazards. Over long follow-up, a survival curve constructed from each causespecific hazard tends to zero, as the number of individuals remaining at risk alive and AIDS-free decreases. If the AIDS events were to occur independently of each other, it is the survival curve that would be observed in the absence of all other competing risks for the outcome, since in this case individuals developing another AIDS disease first would instead be alive and at risk for this specific AIDS-defining disease. A clinically useful quantity is the cumulative probability of developing a specific AIDS-defining event as the first event by time t in the presence of other competing risks (commonly termed cumulative incidence). The overall probability of being alive and AIDS-free at any time equals 1 minus the sum of these cumulative probabilities of having had each specific AIDSdefining disease. The equivalent hazard for each event in the presence of the competing risks can also be considered, corresponding to the sub-distribution for the probability of developing the event in question as the first event. This competing risks hazard can be estimated by effectively censoring individuals who develop a different AIDS-defining disease first at the end of their total follow-up. 20 Estimates from the cause-specific hazard model can be interpreted as the effect of factors on a specific AIDS-defining event in the absence of all other events only by assuming that events occur independently of each other. In reality the degree of dependence between specific events is hard to assess, since even severely immunocompromised people are unlikely to experience more than five or six AIDS-defining events before death over a period of years from their first AIDS diagnosis.

3 CHANGES OVER TIME IN THE RISK OF INDIVIDUAL FIRST AIDS EVENTS 953 However, independence is an unverifiable and unrealistic assumption making the cause-specific model difficult to interpret. In contrast, the competing risks hazard model estimates the effect of factors on the cumulative incidence of specific AIDS-defining diseases, which is intuitively easier to understand. The multivariable analysis of overall progression to AIDS or death included the following variables: exposure category (sex between men, sex between men and women, injecting drug use (IDU), others); age at estimated seroconversion (continuous); sex; presentation during acute HIV infection (a proxy defined by an interval of less than one month between the HIV-negative test and the first HIV-positive test when seroconversion was determined as the midpoint of these dates, 22 or where seroconversion was determined by laboratory evidence); and calendar period at risk as a time-dependent covariate (pre 1991, , , ). Calendar period at risk was used to investigate the population effectiveness of various eras of clinical management including antiretroviral therapy as previously proposed. 3,7,8,14 All studies contributed time at risk to each calendar period after the start of the study. The four calendar periods were chosen to identify the maximum possible impact of; the introduction of PCP prophylaxis and zidovudine monotherapy from mid-1990 onwards; the latest change in AIDS definition in 1993; and the introduction of HAART in 1996/7. Therapy uptake data within CASCADE support the choice of calendar year groups; only 15% of person time at risk in 1990 was spent on zidovudine monotherapy; only 11% in 1993 on dual combination therapy; and only 11% in 1996 on a triple drug regimen containing either a protease or a nonnucleoside reverse-transcriptase inhibitor. The 1993 AIDS case definition was applied from 1993 in most cohorts but not until 1994 in others. Further, some cohorts applied this definition retrospectively. We have used the definition of AIDS as given in the data. For analyses of progression to specific AIDS events (and death without AIDS) there were too few events for some AIDSdefining diseases to fit the models with all levels of the exposure category covariate. In order to compare relative hazards (RH) for calendar year from the same models restricted proportional hazards models were fit only including exposure category as sex between men, IDU and others. Although those exposed through sex between men and women were at significantly greater risk for some specific AIDS-defining diseases, excluding this variable did not substantially alter the estimated effects of the other variables, in particular calendar year at risk. The effect of factors on each specific AIDS-disease as the first AIDS-defining event was modelled separately in cause-specific or competing risks models with a time dependent covariate for calendar year at risk. To compare the effect of calendar year at risk across the specific AIDS diseases, the separate models were stacked into a multivariate model with multiple dependent observations (one for each seroconverter for each specific AIDSdefining disease). Robust variance adjustment within a marginal model framework was used to allow for the fact that each individual contributes more than one observation. 23,24 Wald tests were used to test for heterogeneity across all calendar year periods and within calendar year period. A pre-defined hypothesis was that there would be different temporal changes in the risk of dying without AIDS compared with the AIDS-defining events, so heterogeneity was assessed including and excluding death without AIDS as one of the dependent (outcome) observations in the stacked model. Finally, all the analyses allowed for late entry into the risk set to take into account the lag-time between the estimated date of seroconversion and the date of enrolment into the individual study in order to adjust for possible bias in estimates due to survivorship effect. 25 All analyses were carried out in Stata. 26 Results Of the 6941 subjects included in this analysis who seroconverted between 1979 and 2000, 2021 (29%) progressed to AIDS and 437 (6%) died without an AIDS diagnosis. Of the 6534 seroconverters with a documented negative HIV test date, 89% had an interval of 2 years between negative and positive test dates. The majority of seroconverters were men (80%); the median age at seroconversion was 28 years (range: 15 86); and the most frequent exposure category to HIV was through sex between men (49%), followed by injecting drug use (31%). Table 1 shows the frequency, and the rate per 1000 person years (PY) of each specific AIDS-defining disease as the first AIDS event by calendar period. Overall, the most common AIDSdefining diseases were PCP, candidiasis, and KS. The incidence rates of any first AIDS-defining disease or death without AIDS increased from 48.8 cases per 1000 person-years (PY) in up to 93.6 cases per 1000 PY in followed by a decline in A similar trend over time was observed when death without AIDS was excluded. Several groups of the AIDS-defining diseases (i.e. candidiasis, cryptosporidiosis, CMV, encephalopathy, HSV disease, lymphoma, MAI, PML, TB, and HIV wasting syndrome) showed a similar trend. Other groups (i.e. cryptococcosis, KS, PCP, recurrent pneumonia, toxoplasmosis) showed more complex trends over time, some of which may simply be due to random variation, although the availability and uptake of prophylaxis for some of these opportunistic infections could also play a role. It is of note that there was no substantial decrease in in the group of other AIDS-defining diseases or in deaths without AIDS. However, as the hazard of developing AIDS (or dying without an AIDS diagnosis) is not constant over time following seroconversion, 1 the incidence of specific AIDS events (and of death without AIDS) is confounded with time since seroconversion occurs in each calendar period. Furthermore, this analysis is not adjusted for the effect of other covariates. When we evaluated progression to any AIDS-defining disease or death without AIDS by multivariable Cox model (adjusted for age at seroconversion, sex, exposure category and acute infection), we found that, compared to those at risk in , individuals at risk in had an overall reduced risk of AIDS (RH = 0.32, 95% CI: ) while relatively similar risks were found for those at risk in and (RH = 0.89, 95% CI: ; RH = 0.90, 95% CI: , respectively). Modelling time from HIV seroconversion to each specific AIDS disease as the first AIDS-defining event and death without AIDS using competing risks, there was significant variation in the effect of calendar year overall (P , d.f. = 48). Table 2 shows the estimated RH for each first AIDS-defining disease and death without AIDS by calendar period using as

4 954 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Table 1 Frequency and rate of occurrence of each AIDS-defining disease and death without AIDS in four calendar periods; CASCADE collaboration Calendar period Total Person years at risk First AIDS defining disease or death No. Rate a No. Rate a No. Rate a No. Rate a No. Rate a Any event Any first AIDS defining disease Candidiasis Cryptococcosis Cryptosporidiosis CMV b Encephalopathy HSV c KS d Lymphomas MAI e PCP f PML g Recurrent pneumonia Toxoplasmosis (cerebral) Tuberculosis Wasting syndrome Other AIDS-defining disease h Death without AIDS a Rates (and frequency) for each specific AIDS event as the first AIDS defining event (per 1000 person years). b Cytomegalovirus. c Herpes simplex virus. d Kaposi s sarcoma. e Mycobacterial diseases not including tuberculosis. f Pneumocystis carinii pneumonia. g Progressive multifocal leucoencephalopathy. h Includes: invasive cervical carcinoma, coccidioidomycosis, isosporiasis, salmonella septicaemia and events where the diagnosis was unknown. reference. There was also evidence for variation within each calendar period comparison ( versus : P = 0.009; versus : P = 0.04; versus : P [all d.f. = 16]). Death without AIDS might be expected to be a major factor in this variation. However, when we excluded death without AIDS as an endpoint from the heterogeneity comparison, there was still significant variation in the effect of calendar year overall (P , d.f. = 45), and within each calendar period comparison ( versus : P = 0.006; versus : P = 0.05; versus : P = [all d.f. = 15]). For some AIDS events (i.e. candidiasis, encephalopathy, HSV, KS, toxoplasmosis, and wasting syndrome) we observed a similar pattern in temporal risk changes to that observed for AIDS or death overall; namely virtually no change in risk up to 1996 and substantially decreased risk in For PCP, there was a significant reduction in risk from to (P = 0.001), no change in and then further reduction in A similar pattern was observed for PML and cryptococcosis, but the initial decline from to did not reach statistical significance (P = 0.60 and P = 0.16, respectively). All diseases added to the expanded 1993 AIDS case definition (i.e. pulmonary TB, recurrent pneumonia, and invasive cervical carcinoma) showed increased risk in as expected, in particular the increase in TB reflecting the addition of pulmonary TB to extrapulmonary TB. In contrast to other AIDS-defining events, there was only a modest reduction in the risk of other AIDS diseases as the first AIDS-defining event from to Cytomegalovirus, lymphoma, MAI and cryptosporidiosis also showed an increase from to , no change in , then a reduction in Finally, there was no strong evidence for a change in the risk of death without AIDS over time. The differences between these results and those obtained from a cause-specific model were small for , and (Table 3). In fact, all estimated RH from the cause-specific model differed by 0.1 from those derived from the competing risks model (data not shown). However, the cause-specific RH also suggested the same or larger reductions in risk in than the competing risks RH for all specific AIDS-defining diseases except for TB. It is also of note that the estimated RH in differed most from those obtained using the competing risks model for those AIDS-defining diseases with the smallest risk reductions (Table 3). This would be expected if large reductions in some AIDS-defining diseases led to more seroconverters being at risk for progressing through other AIDS-defining diseases whose incidence had been less affected by HAART. However,

5 CHANGES OVER TIME IN THE RISK OF INDIVIDUAL FIRST AIDS EVENTS 955 Table 2 Effect of calendar year at risk on time from seroconversion to specific first AIDS-defining diseases or death without AIDS Relative hazard First AIDS-defining disease or death N Overall P a Any event or death * Candidiasis * Cryptococcosis Cryptosporidiosis * 0.52* * CMV b * * Encephalopathy * HSV c * 0.02 KS d * Lymphomas * 0.04 MAI e * PCP f * * PML g * Recurrent pneumonia * 0.24* * Toxoplasmosis (cerebral) * Tuberculosis * Wasting syndrome * Other AIDS-defining diseases h Death without AIDS Simultaneously adjusted for sex, age, exposure category (sex between men, IDU, others) and acute infection, and stratified by cohort; * Wald P 0.05 versus a From 2 log partial likelihood test for overall difference across b Cytomegalovirus. c Herpes simplex virus. d Kaposi s sarcoma. e Mycobacterial diseases not including tuberculosis. f Pneumocystis carinii pneumonia. g Progressive multifocal leucoencephalopathy. h Includes: invasive cervical carcinoma, coccidioidomycosis, isosporiasis, salmonella septicaemia and events where the diagnosis was unknown. there was still a significant risk reduction in the majority of AIDS-defining diseases. Discussion Progression to AIDS or death significantly decreased in compared to The impact of HAART is likely to be responsible for at least some of this reduction. 15 However, in studies of population effectiveness of therapies, it is difficult to evaluate the contributory role of other concurrent changes in clinical practice which may be related to outcome, such as frequency of clinic visits or use of prophylaxis for opportunistic infections, 27 even where information on these variables is available. Information on prophylaxis use and health care utilization was not available to CASCADE, and we did not attempt to adjust for changes in patient management. Most importantly, however, we were able to adjust for time since seroconversion, so that differences in the distribution of duration of infection in different calendar periods do not affect our results. The slight non-significant lower risk we found in and in may be due to the extension of the AIDS case definitions in 1987 and in Using a competing risks model, we found a decrease in the risk of all AIDS-defining diseases in except for other rare AIDS events and death without AIDS. A stable trend in the incidence of cervical carcinoma was found in a previously published study, 10 in agreement with the smaller risk reduction in other rare AIDS events (including invasive cervical carcinoma) in CASCADE. However, stable trends in the incidence of non-hodgkin s lymphoma and wasting syndrome reported in that study were not confirmed in CASCADE. This may be merely due to lack of accounting for reduction in the risks of other AIDS-defining diseases as the first AIDS-defining event after the introduction of HAART in that study. However, an alternative explanation for at least part of the rise in the risk of lymphoma previously reported would be provided by the inability of the prevalent cohort to take time from seroconversion into account. A different incubation period for different AIDS-defining diseases together with a prevalent HIV population at different times since seroconversion might affect the apparent changes in the risk of events. The marginally significant decrease in the risk of dying without AIDS observed in our cause-specific model may only be due to the removal of other AIDS-defining diseases as competing risks for progression to AIDS or death. Absolute mortality may also be reduced, but merely at a different rate compared with HIV-related causes. It is likely that the absolute mortality in the absence of an AIDS diagnosis observed in our study is greater than that expected in an equivalent population of HIVnegative individuals. However, studies are needed to investigate

6 956 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Table 3 Percentage risk change of the first specific AIDS-defining diseases in the period compared to : a comparison between a competing risks and a cause specific proportional hazards model Competing risks Cause specific Per cent risk reduction in Per cent risk reduction in First AIDS defining disease compared with (95% CI) Wald P a compared with (95% CI) Wald P a Any event or death 68 (63 72) (63 72) Cryptosporidiosis 96 (81 99) (81 99) PML b 92 (72 98) (74 98) CMV c 90 (77 96) (79 96) Encephalopathy 81 (63 90) (66 91) Wasting syndrome 80 (63 89) (65 90) PCP d 78 (69 85) (70 85) MAI e 77 (50 89) (52 90) KS f 77 (63 86) (65 86) Toxoplasmosis (cerebral) 70 (41 85) (42 85) Candidiasis 70 (59 78) (61 79) HSV g 69 (27 87) (27 87) Recurrent pneumonia 62 (21 82) (26 83) Tuberculosis 59 (32 75) (32 74) Cryptococcosis 56 (20% increase 84% reduction) (1% increase 87% reduction) 0.05 Lymphomas 48 (10 70) (18 73) Other AIDS-defining diseases h 40 (57% increase 77% reduction) (52% increase 77% reduction) 0.27 Death without AIDS 17 (9% increase 37% reduction) (5% increase 39% reduction) 0.10 Multivariable models as Table 2, stratified by cohort. a Wald test for difference in relative risk between and b Progressive multifocal leucoencephalopathy. c Cytomegalovirus. d Pneumocystis carinii pneumonia. e Mycobacterial diseases not including tuberculosis. f Kaposi s sarcoma. g Herpes simplex virus. h Includes: invasive cervical carcinoma, coccidioidomycosis, isosporiasis, Salmonella septicaemia and events where the diagnosis was unknown. whether this is due to other co-infections, such as hepatitis C, as the HIV population has matured, whether it may be related to any side effects of HAART, or whether it is related to psychological effects of HIV (for instance, through increased rates of suicide). Cause of death information is not available within CASCADE. Although the proportional hazards models are based on duration of HIV infection, it is still possible that the increases in the risk of some opportunistic infections, (such as CMV disease and cryptosporidiosis), from to , are partly due to the increasing maturity of the seroconverter cohorts and the associated increased level of immunesuppression. Adjusting for updated CD4 cell counts could, in theory, address this question. However, the CD4 trajectories are likely to capture a substantial part of the possible effect of the therapies available during each calendar period and will thus reduce the effect of calendar year at risk. Such models can therefore only estimate any part of population effectiveness that is not mediated through the CD4 count. Furthermore, the change in AIDS definition in 1993 may have been responsible for the increase in risk observed in for some AIDSdefining illnesses. We estimated a reduction in the risk of PCP after 1990 which is probably associated with the introduction of specific prophylactic treatment as suggested for patients with advanced immune-suppression in that period. 28 The role of prophylaxis appears to be small compared to the role of HAARTcontaining regimens for most opportunistic infections, with the exception of PCP. For example, although cotrimoxazole is suggested to be active against toxoplasmosis, salmonella and pneumonia, yet there is no clear change in the risk of toxoplasmosis as a first event prior to Even in the overall model, we found no change in risk of progression to AIDS or death before , unlike results reported from MACS cohort. 7 It is possible that all AIDS events were under-reported early in the epidemic, although if this were the case we would have also expected to observe a corresponding greater risk of dying without AIDS in the same period. As a decrease in risk is observed for PCP from to , an alternative explanation might be a different partition of AIDS cases across specific AIDS diseases in the US and Europe. The MACS cohort reported a similar pattern in mortality, that is, no decrease from to to that observed in CASCADE. 15 In our analyses, there are a number of limitations and potential sources of bias that may influence results and, therefore, merit discussion. First, all the analyses performed in this study are exploratory, and, clearly, a large number of significance tests are being performed; thus, some effects are likely to arise which may still be due to chance. For example, there is no clear aetiological explanation for an increased risk of PML in , so this may be a chance finding, or due to

7 CHANGES OVER TIME IN THE RISK OF INDIVIDUAL FIRST AIDS EVENTS 957 some kind of ascertainment bias. Second, it is unfortunate that cause of death was not available for the pooled data analysis as it is often not systematically collected within each of the individual cohorts. For a number of seroconverters their AIDS follow-up status was shorter than their survival follow-up status. For example, a person may have last attended a clinic in 1998 and was AIDS-free at the time. In 2000 it became known to the investigators that this person had died but not whether AIDS had been diagnosed in the interim period. In fact, 183 of the 437 (42%) individuals who died without AIDS were last clinically assessed for AIDS status more than 2 months prior to their death. It is possible, therefore, that some of these individuals could have developed AIDS before dying. However, dividing those who died without AIDS into two groups depending on the length of follow up time between last AIDS assessment and date of death ( or 2 months) did not substantially alter results (data not shown). Third, we used the first AIDS-defining illnesses since we did not have information on subsequent events from all cohorts. This may have given rise to results that are conflicting with those of other studies. For example, in contrast to early findings, we found a significant decrease in the risk of lymphoma and of HIV wasting in compared with previous years. A large study has recently reported similar decreases in non-hodgkin s lymphoma. 29 However, our results are based on the first AIDS event only and it is possible that lymphoma could occur more frequently as a subsequent AIDS event. Of the 98 first AIDS diagnoses of lymphoma, 80 were B cell or non-hodgkin s lymphoma and 18 were primary cerebral lymphoma. There was a suggestion that the risk of B-cell lymphoma increased after and then decreased in , whereas the risk of primary lymphoma decreased in and further in Due to small numbers, there was no strong evidence, however, to suggest that the differences between subtypes of lymphoma were real. Further, there was a reduction in risk of both lymphomas in compared with , in both the competing risks and cause-specific models (data not shown). In conclusion, accounting for competing risks provides more precise knowledge on changes in the trend of AIDS-defining illnesses over the time. Some unexpected lack of a decrease in risk of some diseases following the introduction of HAART may be merely due to a differential reduction in the risk of different HIV-related or non-related causes of death. Our data gave similar risk reductions in compared with when competing risks are taken into account and using a causespecific approach. However, the risk reductions observed since the availability of HAART were substantial for the majority of AIDS-defining diseases, particularly the most common. Where dependence between events is much stronger, or where risks of some events actually increases, results from the two models may differ more substantially. Conflicting results may be obtained from different studies due to non-homogeneous methodological approaches. Acknowledgements CASCADE is funded through a grant from the European Union [QLK ] and has received additional funding from GlaxoSmithKline. KEY MESSAGES When considering AIDS as an outcome that has several components, there are two possible approaches to analysis to investigate the effect of factors on time to the specific events making up this endpoint: cause-specific and competing risks hazards. Although the introduction of potent therapy in 1996 has dramatically reduced the risk of AIDS and death, few studies have evaluated this reduction in terms of specific AIDS events and death without AIDS, taking into account the competing risks of other AIDS events. Using pooled data from 6941 HIV-positive individuals with known dates of HIV seroconversion we observed reductions in the risk of most AIDS-defining diseases in compared to These reductions were fairly heterogeneous among the specific events. The estimated risk reductions obtained using a competing risks model were similar to those obtained from a cause-specific model suggesting that, where risk reductions are observed in all or most diseases, and events are not strongly interdependent, the results from the cause-specific and competing risks model may be similar. References 1 Muñoz A, Xu J. Models for the incubation of AIDS and variations according to age and period. 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8 958 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338: Detels R, Muñoz A, McFarlane G et al. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicentre AIDS Cohort Study Investigators. JAMA 1998;17: Dorrucci M, Balducci M, Pezzotti P et al. Temporal changes in the rate of progression to death among Italians with known date of HIV seroconversion: estimates of the population effect of treatment. J AIDS 1999;22: CASCADE Collaboration. Survival after introduction of HAART in people with known duration of HIV-1 infection. Lancet 2000; 355: Moore RD, Chaisson RE. Natural history of HIV infection in the era of combination antiretroviral therapy. AIDS 1999;13: Mocroft A, Katlama C, Johnson AM et al. AIDS across Europe, : the EuroSIDA study. Lancet 2000;356: Ledergerber B, Telenti A, Egger M for the Swiss HIV Cohort Study. Risk of HIV related Kaposi s sarcoma and non-hodgkin s lymphoma with potent antiretroviral therapy: prospective cohort study. BMJ 1999;319: Forrest DM, Seminari E, Hogg RS et al. The incidence and spectrum of AIDS-defining illnesses in persons treated with antiretroviral drugs. Clin Infect Dis 1998;27: Detels R, Tarwater P, Phair JP et al. Effectiveness of potent antiretroviral therapies on the incidence of opportunistic therapies before and after AIDS diagnosis. AIDS 2001;15: CASCADE Collaboration. Changes in uptake of antiretroviral therapy and survival in persons with known duration of HIV infection in Europe. HIV Medicine 2000;1: Anon. Expanded European AIDS case definition. Lancet 1993; 341:441. Appendix Analysis and Writing Committee: Abdel Babiker, Janet Darbyshire, Patrizio Pezzotti, Kholoud Porter, Giovanni Rezza, A Sarah Walker. Steering Committee: Valerie Beral, Roel Coutinho, Janet Darbyshire (Project Leader), Julia Del Amo, Noël Gill (Chairman), Christine Lee, Laurence Meyer, Giovanni Rezza. Co-ordinating Centre: Kholoud Porter (Scientific Co-ordinator), Abdel Babiker, A Sarah Walker, Janet Darbyshire, Freya Tyrer. Collaborators: Aquitaine cohort, France: Francois Dabis, Rodolphe Thiebaut, Sylvie Lawson-Aye; SEROCO cohort, France: Laurence Meyer, Faroudy Boufassa; German cohort, Germany: Osamah Hamouda, Klaus Fischer; Italian Seroconversion Study, Italy: Patrizio Pezzotti, Giovanni Rezza; Greek Haemophilia cohort, Greece: Giota Touloumi, Angelos Hatzakis, Anastasia Karafoulidou, Olga Katsarou; Edinburgh Hospital cohort, UK: Ray Brettle; Madrid cohort, Spain: Julia Del Amo, 17 Cox DR. Regression models and life tables. J R Statist Soc 1972:34: Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York: John Wiley and Sons, Andersen PK, Borgan O, Gill RD, Keiding N. 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Distinguishing efficacy, individual effectiveness and population effectiveness of therapies. AIDS 2000;6: Anon. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR 1992;41(RR-4): Kirk O, Pedersen C, Cozzi Lepri A et al. Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 2001;98: Jorge del Romero; Amsterdam Cohort Study among drug users, the Netherlands: Maria Prins, Roel A Coutinho; Amsterdam Cohort Study on homosexual men, the Netherlands: Birgit van Benthem, Roel A Coutinho; Copenhagen cohort, Denmark: Ole Kirk, Court Pedersen; Valencia IDU cohort, Spain: Ildefonso Hernández Aguado, Santiago Pérez-Hoyos; Oslo and Ulleval Hospital cohorts, Norway: Anne Eskild, Johan N Bruun, Mette Sannes; Royal Free haemophilia cohort, UK: Caroline Sabin, Christine Lee; UK Register of HIV Seroconverters, UK: Anne M Johnson, Andrew N Phillips, Abdel Babiker, Janet H Darbyshire, Noël Gill, Kholoud Porter; Swiss HIV cohort, Switzerland: Patrick Francioli, Philippe Vanhems, Matthias Egger, Martin Rickenbach; Sydney AIDS Prospective Study, Australia: David Cooper, John Kaldor, Lesley Ashton; Sydney Primary HIV Infection cohort, Australia: David Cooper, John Kaldor, Lesley Ashton, Jeanette Vizzard; Badalona IDU Hospital cohort, Spain: Roberto Muga; MRC Biostatistics Unit, Cambridge, UK: Nicholas E Day, Daniela De Angelis.