Introduction
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC virus (JCV), and is generally observed in individuals with cellular immunodeficiency[1]. The first description of PML as an opportunistic disease associated with AIDS dates back to 1982[2]. Concurrently with the HIV epidemic, the prevalence of PML has increased greatly over the past 15 years. From 1991 to 1994, HIV infection was associated with 89% of PML deaths[3]. Before the introduction of protease inhibitors (PI), PML affected between 1 and 4% of all AIDS patients[3-6].
The median survival time after PML diagnosis was approximately 4 months in AIDS patients, before the introduction of PI[6-8]. Recent reports [8-16] suggest that the survival of PML patients improves on combined antiretroviral therapy that includes PI.
In this study, we report the epidemiological features of PML patients included in the French Hospital Database on HIV (FHDH) between 1 July 1995 and 30 June 1997. Our aim is to estimate the change in survival rates, according to the antiretroviral regimen and, in particular, according to whether the regimen included PI.
Patients and methods
The FHDH is a clinical epidemiological network started in 1989 and includes, to date, epidemiological information provided by 29 Centres d‚Information et de Soins de l‚Immunodéficience Humaine (CISIH), which are especially involved in the medical care of HIV-infected persons at 68 French University Hospitals. As of 31 December 1997, the FHDH contained data about 70224 people with HIV infection. Criteria for inclusion in the FHDH are documented HIV infection, follow-up at one of the 29 CISIH, and written informed consent. Trained research assistants used DMI2 software (French Ministry of Health) to collect data at inclusion and at each visit or hospital admission for an HIV-related clinical occurrence or new treatment prescription, or, at least every 6 months. The standardized data collection form includes a description of the transmission group, values of biological markers, clinical HIV-related manifestations according to the Centers for Disease Control (CDC) 1993 revised case definition for clinical AIDS diagnosis, the nature of treatments prescribed, identification of any clinical trials in which the patient participated, and death. The report in the FHDH on data concerning opportunistic complications is consecutive to the validation of such diagnosis in each centre by HIV expert physicians.
The diagnosis of PML is made on the basis of the CDC 1993 revised case definition for clinical AIDS diagnosis. However, there is a consensus in the literature to consider PML diagnosis as definitive on neuropathological criteria or presumptive on clinical and neuroradiological criteria[17]. Moreover, the detection of JCV DNA in the cerebrospinal fluid by polymerase chain reaction (PCR) is currently supplanting brain biopsy for the diagnosis of PML[18,19]. The detection of JCV by PCR in the cerebrospinal fluid has been used widely in French University Hospitals since 1994 as virological criteria. Accurate details about PML diagnosis in France can be found in Gasnault et al.[8].
The current study includes all patients aged at least 15 years with an initial PML episode between 1 July 1995 and 30 June 1997 and a CD4 cell count recorded at the date of PML diagnosis or during the previous 3 months. Inclusion in the study was restricted to PML diagnosed after 1 July 1995, to avoid the selection of long-term survivors. After the baseline PML diagnosis, follow-up was analysed to 31 December 1997.
PI became widely available at the end of March 1996 in France. Therefore, we defined two periods, so that the period before PI availability could be compared with the post-PI period: period 1 ran from 1 July 1995 to 31 March 1996, and period 2, from 1 April 1996 to 30 June 1997. Patients were classified in one of these periods by their date of PML diagnosis. Differences across groups were tested with the Wilcoxon signed-rank test and the χ2 test.
Survival time was calculated from baseline to death or to the last follow-up (censoring date) for patients still alive by 31 December 1997. To take reporting delay into account, we used a censoring method recommended for cohort studies[20]. Patients still alive with a last follow-up in the 6 months before 31 December 1997 (last database update) were censored at 31 December 1997. Kaplan-Meier survival estimates were calculated for the two diagnostic periods. Any difference between the survival curves was tested with the log-rank test.
The crude relative hazards (RH) of death were calculated by Cox‚s proportional hazards model. Patients were classified as antiretroviral-naive or experienced at PML diagnosis. The antiretroviral regimens were analysed as time-dependent covariates to prevent ‚survivor treatment selection bias‚[21-23]. Three time-dependent variables were used: nucleoside reverse transcriptase inhibitor (NRTI) monotherapy (NRTIm) (yes/no), NRTI polytherapy (NRTIp) (yes/no), combination therapy associating PI or a non-nucleoside reverse transcriptase inhibitor (NNRTI) with NRTI (PI/NRTI combination) (yes/no). Each was assessed with an intention-to-continue treatment approach[21-23]. Once having received an antiretroviral regimen and being classified according to that regimen, patients remained in the group despite any subsequent change or discontinuation. Antiretroviral regimen groups were non-exclusive, however, and a patient could have followed different regimens during follow-up.
Other variables tested were age (by 10-year age class), sex, transmission group, CD4 cell count (with a log2 transformation), previous AIDS defining event (ADE) at baseline, and the occurrence of a new ADE during the follow-up (analysed as a time-dependent covariate). All variables for which the P value for the RH of death was less than 0.2 were included in a multivariate model. All Cox‚s models were stratified according to the period of diagnosis.
Statistical analysis used the SAS computer program (version 6.12, Cary, NC, USA).
Results
A total of 246 patients were included in the analysis. During period 1 (1 July 1995 to 31 March 1996), 109 (44.3%) patients were diagnosed with PML, and during period 2 (1 April 1996 to 30 June 1997), 137 (55.7%) patients were diagnosed with PML. Table 1 summarizes the principal characteristics of patients according to the period of diagnosis. The groups were comparable for age at baseline, sex, distribution of transmission groups, AIDS status, and antiretroviral status at baseline. The median CD4 cell count at baseline was significantly higher during period 2 than period 1 (respectively, 53 and 33 cells/μl, P=0.02). In all, 133 patients were treated with PI during follow-up. Two patients received one PI and no other antiretroviral agents; they were classified in the monotherapy category. Of the 131 patients treated with PI as part of a PI/NRTI combination, 76 did not change their antiretroviral regimen during follow-up; 43 were initially treated with NRTIm or NRTIp; 12 patients stopped PI. Four patients received NNRTI during follow-up. As expected, in view of the date when PI became available in France, more patients diagnosed with PML in period 2 were treated with a PI/NRTI combination (Table 1).
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Table 1: Characteristics of patients with progressive multifocal leukoencephalopathy according to the period of diagnosis
By 31 December 1997, after a median follow-up of 4.0 months, a total of 131 deaths were reported (for the period 1 group: 3.3 months, 74 deaths, for the period 2 group: 6.7 months, 57 deaths).
Figure 1 presents the Kaplan-Meier curves for survival after PML diagnosis, according to the period of diagnosis. The probability of survival has improved for patients diagnosed with PML during period 2, compared with those diagnosed in period 1 (log-rank test: P=0.0002). The estimated probability of survival (± standard error) at 6 months was 60.5% (±4.8%) for period 2 and 34.5% (±4.8%) for period 1. The median survival was estimated as 3.5 months for period 1 and was not reached for period 2.
Fig. 1.:
Kaplan-Meier survival estimates of patients with progressive multifocal leukoencephalopathy by period of diagnosis. ------, Period 1, 1 July 1995 to 31 March 1996; ---------, Period 2, 1 April 1996 to 30 June 1997.
Table 2 presents the results of the univariate and multivariate analyses. Sex was not included in the multivariate model because of colinearity with the transmission category. None of the following variables affected survival: age at baseline, sex, transmission group, antiretroviral status at baseline, ADE before PML diagnosis, new ADE after PML diagnosis. In the multivariate analysis, baseline CD4 cell count and antiretroviral regimen during follow-up remained independently associated with the risk of death. A higher CD4 cell count at baseline was associated with improved survival. The efficacy of antiretroviral regimens prescribed during follow-up varied, with the lowest probability of death for the PI/NRTI combination. The NRTIm regimen was not significantly associated with a reduced risk of death. Compared with no antiretroviral regimen, the risk of death was reduced by 38% with NRTIp [RH 0.62, 95% confidence interval (CI) (0.41; 0.95), P=0.026] and by 63% with a PI/NRTI combination (RH 0.37, 95% CI (0.22; 0.64), P=0.0004). Results were similar when we excluded the 12 patients who stopped PI treatment during follow-up (data not shown).
Table 2: Relative hazards of death after progressive multifocal leukoencephalopathy, results of the univariate and multivariate Cox‚s proportional hazards models
Discussion
Despite its increased prevalence since the AIDS epidemic[3], PML is one of the rarest disorders in HIV-infected patients[24], making it difficult to assess without large cohort studies, which are currently lacking. Our study included 246 HIV-infected patients diagnosed with PML between 1 July 1995 and 30 June 1997; 131 of them received an antiretroviral combination that included PI during follow-up.
The study design requires some comments. In our population, the PML diagnosis was both presumptive and confirmed[6,8]. Because diagnostic criteria are not reported patient by patient, we cannot exclude a selection bias (the possibility that other disorders affecting the central nervous system have been reported as PML). However, our study, which was conducted in a short and recent period of time, takes place in the setting of a wide availability of JCV PCR-based PML diagnosis. In the experience of Bicêtre University Hospital, partner of the FHDH, 51 patients were diagnosed with PML between 1995 and 1998, including 40 virologically and six pathologically proven[8]. Moreover, no additional technical improvement occurred in PML diagnosis during the period of the study. Consecutively, it is quite improbable that a selection bias, if any, would affect the two periods of the study differently and thus lead to an overestimation of the effect of combination therapy including PI. Similarly, restrictions on data collection have prevented us from assessing clinical improvement.
Treatments sometimes used for PML, such as cytarabine, alpha interferon, or cidofovir, were not taken into account in our analysis. So far, however, no specific agents have been proved to be efficacious in treating PML[25-27].
We considered 18 patients as lost to follow-up: all had a follow-up of less than 6 months, a last visit before 30 June 1997, and no mention of death by 31 December 1997. A sensitivity analysis assumed that these 18 patients all died the day after their last visit. The results of this analysis were similar to the reported results (data not shown).
One possible bias, described as ‚survivor selection bias‚[21], is that patients who survive longer are more likely to receive treatment, so that any treatment effect may actually reflect only the selection of long-term survivors. We attempted to control for this bias by restricting the period of diagnosis to the period immediately before PI availability and by including antiretroviral regimen categories as time-dependent covariates which is a standard method of preventing such bias[21-23].
Our results showed that survival after PML diagnosis improved substantially among HIV-infected patients who received combination therapy including NRTI and PI, independently of their baseline CD4 cell count. The PI/NRTI combination reduced progression to death by 63% compared with no antiretroviral therapy. This reduction is 1.6 higher than that obtained with NRTI polytherapy. The probability of survival at 6 months for patients diagnosed with PML after 1 April 1996 (date of PI introduction in France) was nearly twice as high as for patients whose PML was diagnosed in the period immediately preceding the introduction of PI (60.5 versus 34.5%). This result should be considered in the light of the rapid spread of this treatment regimen: 77.4% of patients with PML diagnosed after 1 April 1996 were treated with the PI/NRTI combination regimen.
An improvement in PML survival rates, after a combination regimen including PI, has been reported in individuals [9-12] or in small groups of patients[8,13-16]. Remission has been described as being associated with a reduction in the HIV viral load and an increase in the CD4 cell count, which suggests some restoration of an immune response[8-12,15]. Moreover, JCV DNA can become undetectable during follow-up in some previously-positive survivors[8,14,15]. Only one study[28], in 11 patients, failed to observe PML-related benefit from combination antiretroviral therapy including PI.
The response to a regimen of NRTI for patients with AIDS-related PML remains unclear, despite anecdotal reports of improvement associated with high doses of zidovudine[29,30]; but large specific studies were not conducted. In our study, a combination of two or more NRTI was significantly associated with a reduction in the risk of death, compared with no antiretroviral therapy.
The baseline CD4 cell count was a strong independent survival prognosis marker. A higher CD4 cell count was statistically associated with a reduction in the risk of death, consistently with previous reports[7,8,13,16,31].
This study of a large group of patients with AIDS-associated PML provides evidence that antiretroviral combination regimens, particularly combinations including PI, improve survival. At present, an efficient antiretroviral combination regimen should be considered as the best treatment for PML.
Acknowledgements
The authors are grateful to all participants of the cohort, and especially research assistants, without whom this work would not have been possible.
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Appendix
Clinical Epidemiology Group from the French Hospitals Database on HIV
Scientific committee
Alfandari S, Bastides F, Billaud E, Boibieux A, Boué F, Cabié A, Costagliola D, Cotte L, Cuzin L, Dabis F, Daurès JP, Garrait V, Gastaut JA, Gaud C, Grabar S, Goudeau A, Katlama C, Lacoste D, Lang JM, Laurichesse H, Leclercq P, Leport C, Mars ME, Matheron S, Meyohas MC, Michelet C, Moreau J, Pradier C, Quinsat D, Rabaud C, Rozenbaum W, Salmon-Ceron D, Sobesky M, Tissot-Dupont H, Verson R, Viard JP, Waldner-Combernoux A.
Data coordinating centre
INSERM SC4 (Costagliola D, Grabar S, Lièvre L, Marrero L, Mary-Krause M, Tassie JM).
CISIH
Paris area: CISIH de Bichat-Claude Bernard (Hôpital Bichat-Claude Bernard: Matheron S, Aumaître H, Vildé J-L, Leport C, Belarbi L, Bennai Y, Lariveu S, Fournier I), CISIH de Paris-Centre (Hôpital Broussais; GH Tarnier-Cochin: Sicard D, Ginsburg; Hôpital Saint-Joseph: Gilquin J, Cros A), CISIH de Paris-Ouest (Hôpital Necker adultes; Hôpital Laennec; Hôpital de l‚Institut Pasteur), CISIH de Paris-Sud (Hôpital Antoine Béclère; Hôpital de Bicêtre: Khelifa S, Goujard C, Kousignian P; Hôpital Henri Mondor: Lascaux A S, Jung C; Hôpital Paul Brousse: Vittecoq D), CISIH de Paris-Est (Hôpital Rothschild; Hôpital Saint-Antoine: Meynard J-L, Meyohas M-C; Hôpital Tenon), CISIH de Pitié-Salpétrière (GH Pitié-Salpétrière), CISIH de Saint-Louis (Hôpital Saint-Louis: Modaï J, Garrait V, Clauvel J-P, Oksenhendler E; GH Lariboisière-Fernand Widal: Badsi E, Diemer M), CISIH 92 (Hôpital Ambroise Paré: Dupont C, Berthé H; Hôpital Louis Mourier: Michon C, Chandemerle C), CISIH 93 (Hôpital Avicenne: Berlureau P, Jarrousse B, Cohen P; Hôpital Jean Verdier; Hôpital Delafontaine).
Outside Paris area: CISIH Auvergne-Loire (CHU de Clermont-Ferrand: Gourdon F, Beytout J); CISIH de Bourgogne-Franche Comté (CHRU de Besançon: Gil H, Bourezane Y; CHRU de Dijon; CH de Belfort: Egdlinger P, Fall J-P); CISIH de Caen (CHRU de Caen: Bazin C, Verdon R), CISIH de Grenoble (CHU de Grenoble: Bouchard O, Leclercq P), CISIH de Lyon (Hôpital de la Croix-Rousse; Hôpital Edouard Herriot; Hôtel-Dieu: Trepo C, Cotte L; CH de Lyon-Sud: Médecine Pénitentiaire), CISIH de Marseille (Hôpital de la Conception; Hôpital Houphouët-Boigny: Moreau J; Institut Paoli Calmettes; Hôpital Sainte-Marguerite: Gastaut J A, Poizot-Martin I, Grob J-J, Richard M A; Hôtel-Dieu: Gainnier M, Boussuges A; CHG d‚Aix-En-Provence; CH d‚Arles; CH d‚Avignon: Zerazhi M, Touchais A-M; CH de Digne Les Bains: Granet-Brunello P; CH de Gap: Pelissier L, Esterni J-P; CH de Martigues: Nezri M, Ruer J; CHI de Toulon), CISIH de Montpellier (CHU de Montpellier: Reynes J, Baillat V; CHG de Nîmes), CISIH de Nancy (Hôpital de Brabois), CISIH de Nantes (CHRU de Nantes: Raffi F, Milpied B), CISIH de Nice (Hôpital Archet 1: Pradier C, Roger PM; Hôpital Archet 2; Hôpital Cimiez; Hôpital Pasteur; Hôpital Saint-Roch; CHG Antibes Juan les Pins), CISIH de Rennes (CHU de Rennes), CISIH de Rouen (CHRU de Rouen: Gueit I, Caron F), CISIH de Strasbourg (CHRU de Strasbourg: Fischer P, Walter V; Hôpital de Haute-Pierre: Fraisse P; CH de Mulhouse: Beck-Wirth G, Benomar M), CISIH de Toulouse (CHU Purpan: Garbay M-F; Hôpital la Grave; CHU Rangueil), CISIH de Tourcoing-Lille (CH Gustave Dron; CH de Tourcoing: Mouton Y, Ajana F), CISIH de Tours (CHRU de Tours: Bastides F, Besnier J-M; CHU Trousseau).
Overseas: CISIH de Guadeloupe (CHRU de Pointe-à-Pitre), CISIH de Guyane (CHG de Cayenne: Sobesky M, Couppié P), CISIH de Martinique (CHRU de Fort-de-France (Abel S, Cabié A)), CISIH de La Réunion (CHD Félix Guyon).
