- Citado por SciELO
versión impresa ISSN 1698-4447
Med. oral patol. oral cir. bucal (Ed.impr.) v.10 n.1 Valencia ene.-feb. 2005
FERNÁNDEZ-FEIJOO J, DIZ-DIOS P, OTERO-CEPEDA XL, LIMERES-POSSE J, DE LA FUENTE-AGUADO J, OCAMPO-HERMIDA A. PREDICTIVE VALUE OF ORAL CANDIDIASIS AS A MARKER OF PROGRESSION TO AIDS. MED ORAL PATOL ORAL CIR BUCAL 2005;10:32-40.
Objective: To determine the validity of oral candidiasis (OC) as a
clinical marker of progression in patients with human
immunodeficiency virus infection.
Study design: In 1992, an oral examination was carried out on a group of 200 HIV-infected patients with a mean age of 36.8 ± 7 years (range 25-46 years) to establish the diagnosis of OC. The following variables were recorded: age, sex, duration of the disease, risk behaviour, CD4 lymphocyte count, clinical stage and antiretroviral treatment. Of the 200 patients in the group evaluated, 157 did not fulfil the criteria for AIDS at the time of the baseline examination; these patients constitute the study group and underwent 6-monthly follow-up until they fulfilled these criteria. The study was concluded at the end of 2001.
Results: Of the 157 patients selected, 71 (45.2%) did not present OC and, of these, 28.7% progressed to AIDS during the follow-up period. Of the 86 (54.8%) patients with OC, 48.2% progressed to AIDS (RR= 2.71). If the start date of the study was taken as 1997, when highly active antiretroviral therapy (HAART) was introduced, no differences were found in the percentage of patients who progressed to AIDS with respect to the presence or absence of OC at the baseline examination. Multivariate analysis demonstrated that the association of the presence of OC with progression to AIDS did not reach a predictive value.
Conclusions: The long-term prognostic value of OC has not been established in patients receiving highly active antiretroviral therapy (HAART). The immunological recovery and the reduction in the number of opportunistic diseases observed after the administration of HAART means that many patients who developed AIDS do not currently satisfy these criteria, making a review of the definition of the syndrome itself a necessity in order to be able to evaluate prognostic markers.
Key words: Oral candidiasis, HIV, AIDS, progression, prognosis
A large number of clinical, biological and laboratory markers have been used to attempt to predict the progression of HIV infection (1-11). It has been suggested that laboratory markers may only partially reflect the stage and the rate of progression of the disease and that the combination with clinical indicators helps to provide a more global perspective of the patient.
Certain oral lesions associated with HIV infection are considered predictive of progression of the disease (12). Although many studies (13,14-19) have confirmed the prognostic value of oral candidiasis (OC) as an indicator of severe immunosuppression and progression to AIDS, the majority only evaluated the short-term impact of OC before the widespread use of highly active antiretroviral therapy (HAART) and in study groups with a distribution by risk behaviour very different from that observed in our setting.
The aim of the present study has been to analyse the validity of OC as an independent marker of progression to AIDS in a group of HIV-infected Spanish patients followed up over a long period.
MATERIAL AND METHODS
A group of 200 HIV-infected patients from the Infectious Diseases Unit of the Xeral-Cíes Hospital (Vigo) of the Galician Health Service, was evaluated over the first 3 months of 1992 (baseline examination) with the aim of analysing the prevalence and characteristics of OC related to HIV-infection. The final study group was made up of the 157 patients without OC at the baseline visit and included 113 (72%) males and 44 (28%) females with a mean age of 36.8 ± 7 years (range 25-46 years). Patient selection was carried out using the following inclusion criteria: over 18 years of age, diagnosis of HIV infection made by enzyme immunoassay (EIA) and confirmed by Western Blot, and voluntary participation in the study (informed consent). Patients with any of the following characteristics were excluded: the use of antifungal agents for the prophylaxis or treatment of diseases other than OC (Cryptococcosis), severe metabolic or biochemical disturbances, concomitant administration of antibiotics, cytostatics or corticosteroids, and patients with removable acrylic dental prostheses or other factors predisposing to the development of OC (20-34).
Apart from the sex of the patient, a record was also made of the estimated date of seroconversion (defined as the first positive test for antibodies to HIV-1), the duration of the disease (number of semesters from the estimated date of seroconversion to the baseline examination), risk behaviour, clinical category according to the criteria of the Centers for Disease Control in Atlanta (35), the CD4 lymphocyte count and antiretroviral treatment.
Each patient underwent an oral examination at the time of the baseline examination to determine the presence or absence of lesions suggestive of OC, recording the following clinical variables of the OC: pseudomembranous, erythematous, angular chelitis and hyperplastic. Samples were taken from the dorsum of the tongue, the palate and the vestibular buccal mucosa using a sterile swab. When mucosa lesions compatible with OC were observed, an additional sample was also taken from the affected area. All the samples were seeded onto Sabouraud-dextrose agar plates and incubated at 37ºC for 48 hours. Using quantitative criteria, only those cultures with greater than 50 CFU/ml were considered positive. The species of fungi were identified by the Candidafast Unipath and Api 20 C AUX (Biomerieux, Barcelona, Spain) automatic systems. The definitive diagnosis of OC was established using clinical and microbiological criteria (36,37).
A 6-monthly register of progression to AIDS in the group of patients who did not fulfil the criteria for AIDS in January 1992 (n=157), applying the European definition of AIDS (38), was performed from that date until December 2001 (end-of-study). The time to progression to AIDS was defined as the number of semesters from the time of the oral examination until the patient developed any AIDS-defining disease (35). The cumulative time to progression to AIDS was defined as the number of semesters from the estimated date of seroconversion until the patient developed any AIDS-defining disease (35).
Contingency tables were used to study the relationship of the variable of interest (presence or absence of OC) with the other variables recorded at the baseline examination (sex, age, risk behaviour, clinical category, CD4 lymphocyte count and antiretroviral treatment), using these to estimate the prevalence and calculate the relative risks (Risk ratio, RR) and standard errors together with the confidence intervals.
The Cox regression model was applied to estimate the magnitude of the relative risks (Relative hazard, RH) for the different risk factors considered in the study. We estimated the relative risk of the isolated OC variable using a univariate Cox regression model and the effect of the OC was then adjusted for the other study variables using multivariate Cox regression models.
The mean duration of the disease from the estimated date of seroconversion until the time of the baseline examination in 1992 was 4.7 ± 4.2 semesters. With regard to risk behaviour, 112 (71%) belonged to the group of intravenous drug abusers (IVDA), 20 (12.5%) were homosexual men and 25 (16.5%) patients had been infected by heterosexual intercourse.
At the time of the baseline examination, 81 (51.5%) patients were in clinical stage A and 76 (48.5%) in stage B. By CD4 lymphocyte counts, 41 (26%) patients had more than 500/l, 77 (49%) had between 200 and 500/µl and 39 (25%) had less than 200/µl. Only 50.3% of the patients had received antiretroviral treatment in 1992, 75 with AZT and 4 with AZT+ddI.
At the time of the baseline examination, 86 (54%) patients presented OC, 69 (80%) out of them had pseudomembranous lesions, 13 (15.5%) erythematous lesions, 2 had angular chelitis, 1 had hyperplastic candidiasis and 1 case presented mixed clinical findings. The predominant species was Candida albicans (92.5%), with non-albicans spp. (krusei, glabrata, guilliermondii, lambica and parapsilosis) being isolated in the remaining cases.
The prevalence of OC was higher in males than in females (64.3% versus 50.8%), though this difference was not significant (RR=1.26; 95% CI: 0.95-1.67). The time from the date of seroconversion to the baseline examination was 4.8 ± 4.4 semesters in the patients with OC and of 4.4 ± 4.0 semesters in those patients without OC; this difference was not statistically significant. On distribution of the patients into 2 risk behaviour groups, IVDA and infection by sexual intercourse (heterosexual or homosexual), a prevalence of OC of 65.5% in the first group and of 49.1% in the second group was observed. The estimated relative risk of the IVDA group versus the sexual contact group was RR=1.33 (95% CI: 0.99-1.58); this difference was not significant. The relationship of OC with the clinical stage showed an increase in the prevalence of OC with worsening clinical stage. The relative risk of group B versus group A was RR(B/A)=1.51 (95% CI: 1.12-2.03). The relative risk of group C versus group A was RR(C/A)=2.02 (95% CI: 1.53-2.66). In both cases, the RR was significantly greater than 1. The prevalence of OC increased as the CD4 lymphocyte count decreased. In the group with the intermediate CD4 lymphocyte count (200-500/µl), the prevalence of OC was not significantly higher than in the group with the highest lymphocyte count (>500/µl), with a relative risk of RR=1.28 (95% CI: 0.85-1.91); however, the prevalence of OC in the group with a CD4 lymphocyte count <200/µl was significantly higher than in the group with a CD4 lymphocyte count >500/µl, with an RR=1.92 (95% CI: 1.32-2.78). The patients on antiretroviral treatment in 1992 presented a slightly higher prevalence of OC than those not receiving treatment, although this difference was not significant (RR=1.21; 95% CI: 0.96-1.51).
Time to Progression to AIDS
At the time of the baseline examination, 157 of the 200 patients evaluated did not fulfil the criteria for AIDS. Of these 157 pateints, 86 (54%) patients presented OC and 71 (46%) had no clinical lesions. After 20 semesters of follow-up, 48.2% of the patients with OC had developed AIDS compared to 28.7% of those who did not present OC. This difference was statistically significant (p=0.012). The estimated relative risk of progression to AIDS for the patients with OC versus those without OC was RR=1.44 (95% CI: 1.08-1.91) (Figure 1). Between the years 1997 and 2001 (the final 10 semesters of follow-up, covering the period after the introduction of HAART, the frequency of progression to AIDS was 7.7% in the patients with OC and 6.8% in those without OC; the difference between the 2 groups did not reach statistical significance (Figure 2). No statistically significant differences were found in the time to progression to AIDS on consideration of the type of clinical presentation of the OC (pseudomembranous versus the other clinical forms) or the species of Candida isolated (Candida albicans versus other spp.).
The association of the OC variable with progression to AIDS persisted after adjustment for the co-variable of clinical stage (stages A and B) (p=0.007). The risk of progression to AIDS continued to be higher in those patients with OC (RH=2.04; 95% CI: 1.20-3.50). The association of OC and progression to AIDS adjusted for the CD4 lymphocyte count/µl grouped into 3 categories (<200, 200-500, >500) did not reach statistical significance (p=0.051). However, on stratification of the patients by CD4 lymphocyte count the OC maintained its predictive value of progression to AIDS in those patients with CD4 lymphocyte counts >500 /µl (HR=3.30; 95% CI: 1.10-10.20). On bivariate analysis, the variables age, sex, duration of the disease, risk behaviour and antiretroviral treatment did not affect the result and were therefore discarded by the system.
After adjustment for the co-variables described (age, sex, duration of the disease, risk behaviour, clinical stage, CD4 lymphocyte count and antiretroviral treatment), the multivariate analysis showed that the association of the presence of OC with progression to AIDS did not reach a predictive value.
In 1993, the Centers for Disease Control in Atlanta published a modified classification of the definition of AIDS based on a series of clinical markers and a single laboratory indicator, the CD4 lymphocyte count, as the independent definitive criteria (35). The clinical impact of this new definition was shown in a study in which Prins et al (39) analysed the pre-AIDS mortality in patients with HIV infection, demonstrating that the pre-AIDS mortality had reduced considerably in IVDA, suggesting that this could be due to the fact that certain frequent causes of pre-AIDS death in this population, such as pulmonary tuberculosis and recurrent pneumonia, had been incorporated into the expanded definition of AIDS (39). With respect to the CD4 lymphocyte counts, in contrast to the North American experts, the Europeans experts did not include patients with < 200 cells/µl in the expanded definition of AIDS (38) as the application of this criterion would include many asymptomatic individuals in the AIDS stage.
In order to analyse the value of OC as a predictor of progression to AIDS (applying the European criteria), we randomly selected a study group with a distribution of age, sex, risk behaviour, clinical stage and antiretroviral treatment which was found to be very similar to that of HIV-infected patients studied in other regions of Spain in the same period (40).
The exclusion of patients labelled as AIDS cases at the time of starting the study could also constitute a bias, as it has been suggested that these patients, in contrast to those making up the definitive study group, could have been infected earlier or could have been exposed to certain co-factors favouring progression of the disease (41). However, the true time from seroconversion is not known in the majority of cases and is probably very variable. In the absence of this datum, almost all published studies have used the time from the first positive diagnostic test of HIV infection to calculate the duration of the disease and the hypothetical bias has therefore been widely reproduced in the specialist literature and, in consequence, we have used this definition of the estimated date of seroconversion in the methodology section.
It has been demonstrated that OC occurs early in the natural history of HIV infection (42) and its prevalence remains relatively stable for many years thereafter (43). The cumulative incidence of OC (proportion of at least 1 episode of OC during a specified follow-up period) was not recorded as some patients may develop OC during the periods between 2 control visits and receive antifungal treatment from their doctor or initiate this themselves, causing the lesion to disappear by the time of the following examination (42). Furthermore, self-diagnosis of OC has shown limited reliability (42). In consequence, only those lesions present at the single baseline examination performed in 1992 were considered.
As reported by other authors (44), we found no statistically significant differences in the presentation of OC between males and females. As in previous studies (45), the prevalence of OC was higher in the IVDA group.
The rate of progression to AIDS in the present study was higher in the patients with OC than in those without fungal lesions. Before the use of HAART, other investigators such as Katz et al (17), Coates et al (18) and Maden et al (19) had already demonstrated that patients with OC progressed more rapidly to AIDS than those who did not have OC. The presence of OC is considered to be an indicator of immunosuppression (46); at the end of the 80s, Moniaci et al (5), studying a large cohort of Italian patients, observed that OC was associated with low levels of CD4 lymphocytes; this finding was later confirmed in many publications (14-16,47), even in patients who were receiving HAART (48). Using the European definition of AIDS, the finding that OC is related to progression to AIDS is based on the fact that these oral lesions are also predictive of the development of other opportunistic diseases within the space of 3 months (49).
Some authors (47,50) related pseudomembranous OC with advanced stages of the disease and attributed it a greater predictive value for detecting immunosuppression than other clinical presentations (48,51). However, in agreement with other investigators (52), the clinical types of candidiasis did not differentially affect progression to AIDS in the present study.
The patient selection criteria for receiving pharmacological treatment and the efficacy of antiretroviral treatment have changed very substantially over the follow-up period of the present study (53-55). Initially, only the patients with the poorest clinical and immunological status received specific therapy, and the prevalence of AIDS in this group was therefore very high, independently of the presence or absence of OC. The percentage of patients receiving treatment in our series in 1992 was similar to that reported in other publications (56). The proportion of patients receiving HAART at the end of the study was similar in patients with and without OC at the baseline examination (64.7% and 68.5%, respectively).
On analysis of the cumulative time to progression to AIDS, OC maintained its prognostic value. As had already been suggested by Phillips et al (57) and more recently by Hilton (58), the duration of the HIV infection added little value to the risk models for AIDS which include a history of an episode of OC and recency of an episode.
In the multivariate analysis, the presence of OC did not affect progression to AIDS, requiring a study to be performed of the variables which could influence the rate of progression of the infection. Pezzotti et al (59) suggested that the disease progressed more rapidly in older patients; however, the age range in our study group was so limited that the variable was excluded from the system. The sex of the patient does not affect the rate of progression to AIDS (60,61). As it has already been indicated, in the studies of OC there are no substantial differences between the time from the baseline examination and the cumulative time from seroconversion (58). Nor did the risk behaviour of disease transmission appear to affect its course (59). The viral load was not measured in our study since we were unable to perform this measurement in 1992; it is considered that the combination of the HIV-1 viral load and the CD4 lymphocyte count constitutes the best predictor of disease progression (62), but it has been demonstrated that even if OC is associated with high viral loads (63-65), it maintains its prognostic value of progression to AIDS independently of the viral load (66). With respect to antiretroviral therapy, it is clear that even before the introduction of HAART, treatment reduced the long-term risk of progression to AIDS (56). In the present study, OC was a more significant marker of progression than antiretroviral treatment up to 1997; the inclusion of both a pre-HAART period and another post-HAART period in the follow-up has doubtless affected the result, since HAART reduces the number of episodes of OC (67-69) and the rate of progression to AIDS (70).
To-date, no long-term studies have been published on the predictive value of OC in patients treated with HAART. One of its principal inconveniences is derived from the specific definition of AIDS, the static nature of which definitively labels a patient who has suffered any defining disease and presented CD4 lymphocyte counts below 200 cells/µl, independently of their actual state based on the clinical and immunological response to antiretroviral treatment. Our results confirm that OC is not a selective marker of progression to AIDS in patients with access to HAART, in whom it could indicate compliance problems or the development of resistance, and its significance would need to be re-evaluated in a multivariate model. However, this study does confirm its utility for predicting disease progression in those countries without access to laboratory tests or to HAART.
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