Secular trends in the survival of HIV-infected homosexual men in Amsterdam and Vancouver estimated from a death-included CD4-staged Markov model.

BACKGROUND: The purpose of this study was to investigate secular trends in waiting times in CD4-based stages of human immunodeficiency virus (HIV) disease progression in two cohorts of homosexual men, one in Vancouver and one in Amsterdam. All HIV-positive men with two or more CD4 counts in their AIDS-free period between 1 January 1985 and 1 January 1997 were included in this study. Data regarding clinical AIDS diagnoses (using the 1987 Centers for Disease Control and Prevention [CDC] AIDS case definition) and death were collected through active follow-up, review of hospital records, and municipal/national registries. The Vancouver Lymphadenopathy-AIDS Study (VLAS), was started in November 1982 and had enrollment until December 1984. Both HIV-negative and HIV-positive men were followed at intervals of 3-6 months until 1986 and annually thereafter. The Amsterdam cohort study on HIV and AIDS (ACS) started in December 1984, has ongoing enrollment and follow-up of both HIV-negative and HIV-positive homosexual men. The HIV-positive men were followed at intervals of 3 months. METHODS: The CD4-based stage of an individual at each visit was determined using smoothed data. For each cohort and in each calendar time period, a CD4-based Markov model with death as the absorbing stage was fitted to the data. The parameters in this model were estimated using the method of maximum likelihood and confidence intervals were calculated using bootstrap methods. RESULTS: A total of 509 homosexual men participating in the VLAS were included in this study, providing 5356 visits. Some 292 men developed AIDS before 1 January 1997 and 239 died before this date. In all, 232 of the 239 deaths were AIDS related. Thirty-seven per cent of all visits were related to treatment. A total of 543 homosexual men participating in the ACS were included in this study, providing 10 043 visits; 277 men developed AIDS before 1 January 1997 and 250 died before this date. The date of AIDS diagnosis was known for 225 of the 250 deaths. Twenty per cent of all visits were related to treatment. We found that in both cohort studies the stage-specific waiting times were longer in the low CD4-based stages (stages 4, 5 and 6: i.e. CD4 count <500 cells per mm(3)) after March 1990 compared to waiting times before March 1990. The increase in mean waiting time in these stages with low CD4 count was 21%, 33% and 53%, respectively in the ACS and 20%, 2% and 29% in the VLAS. Because waiting times alone are not exclusive for progression in a reversible model we also calculated the stage-specific median incubation periods till death. Men spent considerably longer in these CD4-based stages after March 1990 compared to before March 1990. CONCLUSIONS: Data from these population-based cohort studies showed that HIV disease progression in the calendar period where treatment was administered was slower for individuals in stages with low CD4 counts. We found no evidence for shortening of the incubation period that may have appeared from increasing virulence of the HIV in the population.

The incubation period to AIDS in injecting drug users estimated from prevalent cohort data, accounting for death prior to an AIDS diagnosis.

OBJECTIVE: To estimate the incubation-period distribution (time from seroconversion to AIDS) accounting for death before an AIDS diagnosis (DBAD) in a cohort of injecting drug users (IDU) in Amsterdam, The Netherlands and to compare these estimates with those previously obtained from a contemporaneous study of homosexual and bisexual men in Amsterdam carried out using the same facilities. DESIGN: Participants in a cohort study begun in Amsterdam at the end of 1985 have scheduled follow-up visits every 4 months. All participants of Dutch nationality and who had two or more follow-up visits before January 1996 from which CD4 measurements were available were included in this study. Data concerning AIDS diagnosis and death were verified through review of national and municipal registries. METHODS: Because time of seroconversion was unknown for study participants and because IDU are at substantial risk for DBAD, we used a Markov model with CD4-based stages that allows for DBAD. The parameters in this model were estimated using the method of maximum likelihood and confidence intervals were calculated using bootstrap methods. RESULTS: A total of 173 IDU (134 seroprevalent, 39 seroincident) made 1829 visits. Nearly 10% of the visits were non-consecutive. Forty-five IDU developed AIDS and 25 died without an AIDS diagnosis. We estimated that 24% [95% confidence interval (CI), 17-25%] of IDU die before an AIDS diagnosis. As a result, the median time from seroconversion to AIDS (10.5 years; 95% CI, 9.1-10.7 years) is considerably longer than the median time from seroconversion to death (8.3 years; 95% CI, 7.9-8.5 years). Conditional on survival to an AIDS diagnosis, the median time to AIDS is 8.2 years (95% CI, 7.7-8.7 years). The median survival time after a diagnosis of AIDS is estimated to be 1.0 years. CONCLUSION: The high occurrence of DBAD in IDU has a considerable influence on estimates of the incubation-period distribution. Progression from seroconversion to death was faster in the IDU cohort than in a cohort of homosexual men in Amsterdam (median, 8.3 years and 9.6 years, respectively). However, progression to AIDS conditional on survival to an AIDS diagnosis seems to be similar in both the IDU cohort and in the cohort of homosexual men (median, 8.2 years and 8.3 years, respectively).

Use of immunological markers and continuous-time Markov models to estimate progression of HIV infection in homosexual men.

OBJECTIVES: We used continuous-time Markov models based on CD4 cell counts and anti-CD3 reactivity (i.e., measure for T-cell quality) to study the progression of HIV infection in a cohort study of homosexual men in Amsterdam. We also compared the effectiveness of anti-CD3 reactivity as a marker for disease progression with that of CD4 cell counts. METHODS: We used data from 467 men (6905 visits) with visits at 3-month intervals between October 1984 and March 1993. To account for measurement error and short time-scale variability, the immunological stage at each visit was determined using a kernel smoother on log-transformed data from each individual. The Markov model had six marker-defined stages and a seventh stage for clinical AIDS. The initial stage-occupation probabilities for seroconverters were used to estimate the incubation time from infection to AIDS. Confidence intervals were calculated using the bootstrap method to account for the effect of smoothing on the variability of our estimates. RESULTS: The CD4 staging scheme estimated the median time from seroconversion to AIDS at 8.3 years [95% confidence interval (CI), 8.1-8.6], and a similar estimate was obtained with the anti-CD3 staging model. The CD4 model predicts that 10.2% (95% CI, 9.9-13.1) will remain AIDS-free 15 years after seroconversion. The mean number of stages visited before AIDS is lower with the CD4 model (7.4; 95% CI, 7.2-7.7) than with the anti-CD3 model (11.3; 95% CI, 10.8-12.0), implying that anti-CD3 predicts progression less well than CD4 cell count. CONCLUSIONS: CD4 lymphocyte counts and anti-CD3 reactivity are each associated with an increased hazard for progression to AIDS. Therefore, men in different CD4-stages (anti-CD3 stages) follow different incubation period distributions to AIDS. However, anti-CD3 predicts progression less well than CD4 cell count. Staged time-continuous Markov models are useful to study immunological markers for HIV disease progression.

The treatment-free incubation period of AIDS in a cohort of homosexual men.

OBJECTIVE: The treatment-free incubation period distribution was estimated from data obtained from a cohort of homo/bisexual men in Amsterdam. DESIGN: Participants in a cohort study that started in Amsterdam at the end of 1984 were seen at 3- or 6-monthly intervals. The analysis excluded time since the start of zidovudine treatment (given to 27 individuals) and no cohort member received primary Pneumocystis carinii pneumonia prophylaxis (i.e., before AIDS diagnosis) before February 1990. METHODS: Both HIV-positive (n = 269) and HIV-seroconverted (n = 79) homosexual men were included in this study. Of these, 68 developed AIDS before February 1990. The unobserved dates of seroconversion were obtained by multiple imputation. The incubation period distribution was estimated from these data by direct Kaplan-Meier analysis and by using parametric Weibull and gamma distributions (including a parameter describing the probability of never progressing to AIDS). Our results are compared with published estimates of progression to AIDS from other homo/bisexual cohort studies. RESULTS: Both the Weibull and the gamma distributions provide equally good empirical descriptions of the incubation period distribution for up to 7 years postseroconversion, but the estimated gamma distribution (median, 9.2; mean, 10.2; percentage AIDS at 7 years, 33%) should be preferred beyond that time, due to a slowing of the hazard rate. There is insufficient information to be able to estimate accurately the probability of never progressing to AIDS. CONCLUSIONS: The time-dependent pattern of HIV incidence should be considered in the analysis of prevalent cohort studies. Our results are in agreement with other homo/bisexual cohort studies, and will be valuable for future comparison with and understanding of the epidemiological consequences of clinical treatment that delays the onset of AIDS.

Subacute sclerosing panencephalitis in The Netherlands--1976-1990.

Since 1976, when general immunization against measles was introduced in the Netherlands, all new cases of subacute sclerosing panencephalitis (SSPE) were registered and detailed data about immunization, epidemiology and disease progression were collected on them. Up to 1991, 99 new patients have been registered of which 81 were born in this country and 18 elsewhere. From 1981 onwards, the incidence of SSPE among those born in the Netherlands decreased gradually from 13 cases per year to one case per year. This decrease is attributed to the large scale of immunization against measles. Three SSPE patients had been immunized against measles, all of them without a history of clinical measles. Epidemiology and risk factors of SSPE did not differ from those reported in other countries. An exceptional cluster of four patients in one town, who had measles in the same year, is reported. Progression of SSPE appeared to be age related. A total of 28 patients was treated with Inosiplex; no significant effect on survival in stage 3 of the disease was found.

Enzymatic profiles of Enterobacter sakazakii and related species with special reference to the alpha-glucosidase reaction and reproducibility of the test system.

The enzymatic profiles of Enterobacter sakazakii, Enterobacter cloacae, Enterobacter aerogenes, and Enterobacter agglomerans were determined with the API ZYM system (API System S.A., La Balme Les Grottes, France). Each assay was performed three times. A simple formula was derived and applied to assess the reproducibility of the API ZYM tests. In addition, a separate alpha-glucosidase test was performed. All E. sakazakii isolates produced alpha-glucosidase, in contrast to the other Enterobacter isolates. No phosphoamidase activity was detected in any of the E. sakazakii isolates, whereas it was present in 72% of E. cloacae, 89% of E. agglomerans, and 100% of E. aerogenes isolates. It was concluded that detection of alpha-glucosidase permits rapid and reliable differentiation between E. sakazakii and other Enterobacter species. The reproducibilities of alpha-glucosidase and phosphoamidase reactions were estimated to be 89 and 81%, respectively.