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Oral Lesions as Clinical Markers of Highly Active Antiretroviral Therapy Failure: A Nested Case-Control Study in Mexico City

  1. Velia Ramírez-Amador1,
  2. Sergio Ponce-de-León2,
  3. Gabriela Anaya-Saavedra1,
  4. Brenda Crabtree Ramírez2, and
  5. Juan Sierra-Madero1
  1. 1Universidad Autónoma Metropolitana-Xochimilco, Mexico City, Mexico
  2. 2Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
  1. Reprints or correspondence: Dr. Velia Ramírez-Amador, Universidad Autónoma Metropolitana-Xochimilco, Camino Sta. Teresa 277-9, Col. Parques del Pedregal, Mexico D.F. 14010 (rava1863{at}correo.xoc.uam.mx).
 
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Abstract

Background. Clinical markers that may predict virological failure during highly active antiretroviral therapy (HAART) have not been evaluated adequately. The aim of the present study was to evaluate the usefulness of human immunodeficiency virus (HIV)–related oral lesions as clinical predictors of virological failure in HIV-infected patients receiving HAART.

Methods. A nested case-control study was conducted within a cohort of 1134 HIV-infected patients receiving HAART who attended the AIDS Clinic of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City during the period 1997–2005. Case patients were patients who, after achieving an undetectable viral load, had at least 1 viral load determination ⩾2000 copies/mL while receiving treatment. Control subjects were patients who, after achieving an undetectable viral load, continued to have undetectable viral loads during the follow-up period. There were 2–3 control subjects for each case patient, matched according to duration of follow-up. Oral examinations were blinded to viral loads and CD4+ lymphocyte counts. Analyses were performed with multivariate conditional logistic regression models, and associations were shown as odds ratios (ORs) with 95% confidence intervals (CI). Positive predictive values were calculated.

Results. The target cohort consisted of 431 HIV-infected individuals; 47 case patients and 132 control subjects underwent complete oral examinations and formed the basis of the analysis. At the visit at which an undetectable viral load was determined, case patients and control subjects showed a similar frequency of HIV-related oral lesions (21.3% vs. 17.4%) (OR, 1.39; 95% CI, 0.57–3.38; P = .47). At the visit at which virological failure was determined, case patients showed a higher risk for HIV-related oral lesions (OR, 14.5; 95% CI, 4.21–49.94; P < .001) and oral candidosis (OR, 26.2; 95% CI, 3.34–205.9; P < .001) than did control subjects. The positive predictive value of HIV-related oral lesions and oral candidosis to identify patients who experienced virological failure while receiving HAART was 80% and 83%, respectively.

Conclusions. HIV-related oral lesions and, specifically, oral candidosis may be considered to be clinical markers of virological failure in HIV-infected patients receiving HAART.

Clinical course in HIV-infected patients is assessed by means of CD4+ lymphocyte counts and viral load (VL) measurements, which are considered to be accurate predictors of HIV disease progression [1]. Moreover, VL monitoring is necessary to ensure adequate response and to guide opportune changes in therapy before drug resistance develops [2, 3].

The association of certain HIV-related oral lesions (HIV-OLs), such as oral candidosis and hairy leukoplakia, with decreased CD4+ lymphocyte counts [4, 5] and increased VLs in HIV-infected adult subjects has been clearly demonstrated in numerous studies [4, 6,7,8,9,10–11]. In addition, a recent longitudinal study has suggested that the onset of oral candidosis and hairy leukoplakia was associated with a progressive reduction in CD4+ lymphocyte count and an abrupt increase in VL [7]. Clinical markers that may predict virological failure during HAART have not been evaluated adequately. Because oral lesions are well-established markers of HIV disease progression, we hypothesize that these markers could be useful to predict virological failure in patients receiving HAART. Clinical predictors of virological failure, such as oral lesions, may help detect cases of virological failure in resource-limited settings where laboratory tests are not widely available or are too costly to be performed on a regular basis.

Thus, we decided to conduct this nested case-control study to evaluate the usefulness of HIV-OLs as clinical predictors of virological failure in a group of Mexican HIV-infected adult patients receiving HAART.

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Patients and Methods

We conducted a nested case-control study involving a cohort of 1134 HIV-infected patients treated with HAART at the AIDS Clinic of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City, Mexico. Demographic (i.e., sex, age, education, and socioeconomic status) and clinical (i.e., stage of HIV infection, route of transmission, HAART regimen, CD4+ lymphocyte count, and VL) data were obtained from the database of the AIDS clinic, which contained data collected in a prospective manner from April 1997 through May 2005, as well as data from medical charts. Socioeconomic status classification was based on the ad hoc institutional system, which ranks patients for the purpose of establishing their payment ability on a scale from 1 (least able to pay) through 7 (most able to pay).

Oral medicine data (i.e., history of HIV-OLs, tobacco use, and HIV-OLs at baseline and at follow-up visits) were collected from the database of the Oral Medicine and Pathology clinic at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; the database was implemented in 1990 and prospectively evaluated all HIV-infected patients at their AIDS clinic visit. During these visits, a structured oral examination was conducted by trained personnel, including 2 of the authors (V.R.-A. and G.A.-S.). Standardized criteria for the diagnosis of HIV-OLs were followed [12]. According to the recommendations of the EC Clearinghouse criteria [12], HIV-OLs are classified into 3 groups: those strongly associated with HIV infection; those less commonly associated with HIV infection; and those seen in, but not indicative of, HIV infection. Our study included the following oral mucosal lesions from the first group: pseudomembranous candidosis, erythematous candidosis, and oral candidosis (which is either pseudomembranous candidosis, erythematous candidosis, or both); hairy leukoplakia; periodontal disease, which involves linear gingival erythema, necrotizing ulcerative gingivitis, and necrotizing ulcerative periodontitis; Kaposi sarcoma and non-Hodgkin lymphoma. From the second group, lesions due to viral infections (e.g., infection due to herpes simplex virus), labial and intraoral lesions, and lesions associated with human papillomavirus (e.g., warty lesions) were included. From the third group (lesions seen in, but not indicative of, HIV infection), recurrent aphthous ulcers were included. Hyperplastic candidosis was also incorporated into our study.

Individuals who achieved an undetectable VL (<50 copies/mL) after initiation of a new HAART regimen (either a first or subsequent regimen), had a baseline VL determination, and had at least 1 additional follow-up VL measurement after achieving an undetectable VL were eligible for the study. Patients who had treatment interruptions and patients who did not have the minimum number of VL measurements were excluded.

Case patients were patients who, after achieving an undetectable VL, experienced virological failure, defined as having at least 1 VL measurement of ⩾2000 copies/mL while receiving treatment. Subjects who experienced an isolated rebound, achieving a VL of <2000 copies/mL, were considered to have experienced a VL “blip”and were not included in this analysis. Selected case patients were patients who underwent complete oral examinations, defined as 1 oral examination performed at approximately the same time as the baseline VL determination, a second oral examination performed at approximately the same time as the first undetectable VL determination, and a third oral examination performed at approximately the same time that an increased VL was observed. The follow-up period for the case patients was the period from the first undetectable VL measurement through the determination of a VL >2000 copies/mL.

Control subjects were patients who, after achieving an undetectable VL, continued to have undetectable VLs throughout follow-up. For each case patient, 2–3 control subjects were selected, matched by follow-up duration that was comparable to or longer than the duration of follow-up for the matched case patients. Complete oral examinations for control subjects were defined as 1 oral examination performed at approximately the same time as the baseline VL determination, a second oral examination performed at approximately the same time as the first undetectable VL determination, and a third oral examination performed at approximately the same time as a subsequent undetectable VL determination.

Oral examinations of case patients and control subjects were independently performed and blinded to VL data and CD4+ lymphocyte counts. Oral candidosis was confirmed by the demonstration of Candida species in cytological smear specimens stained by periodic acid-Schiff technique. The diagnosis of hairy leukoplakia was confirmed by the absence of response to antifungal therapy [12].

HAART was defined as therapy with any combination of antiretroviral drugs that included at least 2 nucleoside reverse-transcriptase inhibitors and 1 protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor or that included a protease inhibitor and a nonnucleoside reverse-transcriptase inhibitor. Also, the combination of 3 nucleoside reverse-transcriptase inhibitors was considered to be HAART [2].

A successful HAART regimen was defined as a HAART regimen administered to a patient who achieved VL suppression and attained an undetectable VL. Duration of HAART was the period from the initiation of the successful HAART regimen through the achievement of an undetectable VL.

Descriptive data for case patients and control subjects were summarized with conventional central tendency indexes. To look for possible associations between HIV-OLs or potential confounders and the development of virological failure, we calculated simple conditional logistic regression models using the matched sampling procedure. If an association was identified, multivariate conditional logistic regression models were built that included the suspected factor and confounders, such as socioeconomic status and clinical stage of HIV infection. Association results are shown as ORs and 95% CIs.

To better evaluate the potential response marker role of the diverse HIV-OLs, positive predictive values were calculated from the quotient of case patients with treatment failure who were affected by a given type of oral lesion divided by the total number of case patients and control subjects with that same type of oral lesion. Prevalence of treatment failure was determined for the underlying cohort. For the binomial distribution, 95% CIs were calculated. All analyses were performed using Stata software, version 7.0 (Stata).

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Results

In the present study, the target cohort consisted of 431 HIV-infected individuals; 109 (25.3%) fulfilled the definition criteria for case patients, and 322 (74.7%) fulfilled the definition criteria for control subjects (figure 1). Forty-seven case patients and 132 control subjects underwent complete oral examinations performed and formed the basis of the analysis. Three subjects who experienced VL “blips” (as defined in the Patients and Methods section) were not included in this analysis. Case patients (62 patients) and control subjects (190 patients) who did not undergo an oral examination were similar at baseline to those who were included in the study with regard to sex, age, socioeconomic status, transmission category, number of HAART regimens, median CD4+ lymphocyte counts (nadir and baseline), and baseline VL; however, among control subjects, patients who underwent complete oral examinations had a higher level of education than patients who were not included in the study (P < .001). Case patients and control subjects included in the study were more likely to have an advanced stage of HIV infection than were individuals who did not undergo complete oral examinations; the difference was statistically significant only for the control subjects (P = .02), not for the case patients (P = .13).

Figure 1
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Figure 1

Flow diagram for study subjects from the source cohort to the target cohort. OFU, oral follow-up.

Complete oral examinations were performed within a median duration that included time before or after the VL determination; for case patients and control subjects, oral examinations were performed within a median of 30 days (interquartile range [IQR], 0–79 days) of the baseline VL measurement and within a median of 8 days (IQR, -24 to 34 days) of the first undetectable VL measurement. For case patients, a third oral examination was performed within a median of 14 days (IQR, 4–42 days) before or after the determination of an increased VL. Control subjects had a third oral examination performed within a median of 15 days (IQR, 7–33 days) before or after a subsequent undetectable VL was observed. The median period between the first undetectable VL and determination of virological failure was 360 days (IQR, 224–643 days).

Case patients and control subjects were similar with respect to demographic characteristics; individuals were predominantly male, predominantly from the middle socioeconomic level, and had a mean duration of education of 9 years. The socioeconomic status classification showed that individuals with higher socioeconomic status had a reduced risk of HAART failure, compared with individuals with lower socioeconomic status (table 1).

Table 1
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Table 1

Demographic and clinical data for 179 HIV-infected patients.

With respect to clinical characteristics, most study subjects had experienced transmission through male-male sex and had advanced disease (defined according to the Centers for Disease Control and Prevention clinical disease stage categories); the rate of tobacco exposure was ∼40%. The median nadir CD4+ lymphocyte count for case patients and control subjects was <100 cell/mm3 (table 1).

Almost one-half (41.9%) of the individuals in the study had previously received HAART (case patients, 53.2%; control subjects, 37.9%). The median duration of effective HAART until an undetectable VL was achieved was similar for both groups (case patients, 133 days [IQR, 84–254 days]; control subjects, 183 days [IQR, 110–356]; P = .33).

Case patients and control subjects were similar with respect to history of HIV-OLs (68.1% and 58.3%, respectively; OR, 1.47; 95% CI, 0.76–2.82; P = .25). As shown in table 2, the most common HIV-OLs for all visits were oral candidosis (predominantly the erythematous type), hairy leukoplakia, and recurrent oral ulcers; however, other oral lesions, such as those caused by viral infections (e.g., infections due to herpes simplex virus and human papillomavirus), periodontal disease (e.g., linear gingival erythema and necrotizing ulcerative gingivitis), and hyperplastic candidosis (in 1 case patient) were also identified. In addition, no associations were found between HIV-OLs and the risk of virological failure at baseline (OR, 0.95; 95% CI, 0.50–1.84; P = .89) or at the first visit after an undetectable VL was achieved (OR, 1.39; 95% CI, 0.57–3.38; P = .46). Median CD4+ lymphocyte counts were similar for case patients and control subjects at the first visit after an undetectable VL was achieved (220 cell/mm3 and 252.5 cell/mm3, respectively); the difference was not statistically significant (P = .15).

Table 2
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Table 2

HIV-related oral lesions during follow-up.

In contrast, at the visit at which virological failure was determined, patients with HIV-OLs showed a higher risk for HAART failure (OR, 14.5; 95% CI, 4.2–49.9; P < .001) than did those without oral lesions (table 2). The OR for HAART failure in the patients who developed oral candidosis was 26.2 (95% CI, 3.3–205.9; P = .002). In addition, the rate of treatment with antifungal drugs was higher among case patients (19.1%) than among control subjects (3.0%; OR, 10.4; 95% CI, 2.2–48.9; P = .003). At the time of virological failure, case patients showed a median VL of 22,300 copies/mL (4.4 log10 copies/mL) and had a significantly lower median CD4+ lymphocyte count (251 cell/mm3) than did control subjects (355 cell/mm3; P < .001).

Multivariate models showed no association between virological failure and baseline characteristics, including with simultaneous control for educational level, socioeconomic status, previous HIV-OLs, clinical stage, presence of HIV-OLs at baseline, VL and CD4+ lymphocyte counts at baseline, and nadir CD4+ lymphocyte count (pseudo R2 = 0.07; P = .83). There was no association between virological failure and oral lesions, VL levels, or CD4+ lymphocyte counts at the visit at which undetectable VL was determined (pseudo R2 = 0.02; P = .31). Finally, virological failure was significantly associated, in simultaneous analysis, with both HIV-OLs and CD4+ lymphocyte counts at the final visit (pseudo R2 = 0.37; P < .001); values are shown in table 3.

Table 3
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Table 3

Multivariate conditional logistic regression of virological failure with CD4+ lymphocyte counts and HIV-related oral lesions at final visit.

Assuming that the prevalence of virological failure in our cohort was 26.3%, the positive predictive values associated with the most common HIV-OLs are displayed in table 4. The presence of HIV-OLs after an undetectable VL was achieved was associated with a significant increase in the predicted virological failure rate, from 26.3% to 80%.

Table 4
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Table 4

Positive predictive value of the presence of HIV-related oral lesions as predictors of virological failure (assuming a prevalence of virological failure of 26.3%).

The results for HIV-OLs and oral candidosis are remarkable, given that the lower limits of the 95% CIs clearly exclude the a priori probability of virological failure of 26.3%. On the other hand, the 95% CIs for hairy leukoplakia and recurrent oral ulcers are quite wide, which means that, at least on the basis of present results, they are not clear, strong predictors of virological failure.

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Discussion

Even though there is strong evidence that HAART significantly reduces the prevalence of oral manifestations of HIV infection [4, 8, 13,14,15–16] and a large amount of data related to the use of HIV-OLs as clinical markers of disease progression [4, 17,18–19], studies evaluating the use of HIV-OLs as markers of virological failure during HAART are limited. This is, to our knowledge, the first study that clearly demonstrates a strong temporal association between HIV-OLs, particularly oral candidosis, and virological failure in HIV-infected patients who have previously been successfully treated with HAART. Patients with HIV-OLs showed a significantly greater risk for HAART failure (OR, 14.5; 95% CI, 4.2–49.9; P = .005); the risk was particularly high for patients with oral candidosis (OR, 26.2; 95% CI, 3.3–205.9; P = .002).

Moreover, the positive predictive values for the ability of HIV-OLs and oral candidosis to identify patients who experienced virological failure while receiving HAART was high in the present study (80% and 83%, respectively), compared with a previous report [20] in which oral candidosis was associated with a positive predictive value of 52.8% at baseline and 41.7% after 6 months of follow-up. Also, the presence of concurrent lesions (oral candidosis and hairy leukoplakia) has been reported to be associated with a positive predictive value of 60% for a VL ⩾20,000 copies/mL [21].

Two previous studies have attempted to evaluate the association of HIV-OLs with immunological and virological failure [20, 22]. A cross-sectional study involving 151 Spanish patients with HIV infection and/or AIDS who were receiving HAART showed that only the presence of oral candidosis was related to immunological failure [22]. In addition, a prospective study involving 124 Brazilian patients with HIV infection and/or AIDS who were receiving HAART demonstrated that oral candidosis was associated with a positive predictive value of 66.7% for the outcome of CD4+ lymphocyte count <200 cells/mm3 and 41.7% for an outcome of VL ⩾20,000 copies/mL [20]; in contrast, hairy leukoplakia was associated with moderate positive predictive values for both measures.

In our study, after effective HAART, both groups of patients showed a marked reduction in the prevalence of HIV-OLs (from 42.5% to 21.3% for case patients and from 43.9% to 17.4% for control subjects) as a result of the immune reconstitution achieved after a median duration of HAART (case patients, 133 days; control subjects, 183 days). Similar findings have been reported in numerous studies, such as a previous study from our group that showed a decrease of 50% in HIV-OLs in patients receiving HAART [15]; other studies have shown reductions of 56% in the United States [16], 46% in Spain [23], and 24% in the United Kingdom [24].

The design of this nested case-control study allowed us to evaluate how, in patients with HIV infection who are receiving HAART, HIV-OLs are associated with the onset of virological failure. This research design combines the advantages of a prospective cohort study [25,26–27] in which information was obtained prospectively from 1997 through 2005 with those of the so-called case-control design, resulting in a higher efficiency in identifying the impact of a feature or exposure.

Also, it is important to highlight that, in our cohort, virological failure, as defined in Patients and Methods, was meticulously distinguished from other causes of increased VL, such as HAART interruptions associated with toxicity. In addition, it is relevant to emphasize that oral examinations were performed independently and were performed by health care personnel who were blinded to VL measurements and CD4+ lymphocyte counts.

A limitation of the study was that, from the original cohort of 1134 HIV- infected patients, a significant number (529 patients; 46.6%) did not have complete VL determinations. In addition, only 179 (41.5%) of the 431 individuals in the target cohort had complete oral examinations performed. Considering the high number of patients with inadequate follow-up data, we performed a comparison between enrolled and nonenrolled patients; as a result, we found that both groups were similar, except in terms of educational background and severity of disease. Because schooling was better and disease more severe among patients who were enrolled in the study, we conclude that these features may be markers of a better compliance with medical (including oral) care. However, this bias did not seem to affect the main conclusion of the study, because these variables are not related to the main outcome (i.e., virological failure).

Our results suggest that oral candidosis may be considered to be a good clinical marker of virological failure in HIV-infected patients receiving HAART, which agrees with the findings of other authors, who have demonstrated that oral candidosis is a better predictor of virological failure than hairy leukoplakia [20, 28]. According to Flint et al. [13], oropharyngeal candidosis fulfills 3 of the criteria for a useful marker of HIV disease progression following HAART failure: the lesion is not sex specific, it is an early sign of HIV infection in the erythematous form, and its prevalence correlates to VL.

Various studies have also demonstrated a strong correlation between high VL and oral candidosis [9, 28, 29], and others have found a significant relationship between increased VL and both oral candidosis and hairy leukoplakia [7, 8, 11, 21, 30,31,32,33–34].

Miziara and Weber [20] have found a slight association between hairy leukoplakia and virological failure in patients receiving HAART. Moreover, the presence of hairy leukoplakia has been associated with high and medium VLs [35, 36]. In contrast, Gaitan-Cepeda et al. [22] have suggested that hairy leukoplakia should not be considered to be a predictive marker of virological failure, because no relationship was found between virologic failure and the presence of hairy leukoplakia in their investigation. To determine the relevance of hairy leukoplakia as a clinical predictor for virological failure in our study, a larger number of patients would have been necessary.

HIV-OLs have demonstrated usefulness as indicators of disease progression and as a tool for monitoring HIV infection in conjunction with CD4+ lymphocyte count and plasma VL. Our study proposes that oral lesions, especially oral candidosis, may be considered to be clinical markers of virological failure in HIV-infected patients receiving HAART. The onset of HIV-OLs, particularly oral candidosis, should alert the clinician to confirm virological failure with the appropriate laboratory testing. Clinical evaluation should not be a substitute for periodic VL measurements; however, it could be an additional tool for the clinician, especially in resource-limited settings, where VL assays may not be widely available.

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Acknowledgments

We thank Pedro Hernández Rodríguez and Marco Antonio Servín García for their considerable assistance in data retrieval.

Potential conflicts of interest. All authors: no conflicts.

  • Received March 18, 2007.
  • Accepted June 4, 2007.
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References

  1. ↵
    1. Mellors JW,
    2. Muñoz A,
    3. Giorgi JV,
    4. et al
    . Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997;126:946-54.
    Abstract/FREE Full Text
  2. ↵
    1. US Department of Health and Human Services
    . Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf Accessed 27 February 2007.
  3. ↵
    1. Hammer SM,
    2. Saag MS,
    3. Schechter M,
    4. et al
    . Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA Panel. JAMA 2006;296:827-43.
    Abstract/FREE Full Text
  4. ↵
    1. Hodgson TA,
    2. Greenspan D,
    3. Greenspan JS
    . Oral lesions of HIV disease and HAART in industrialized countries. Adv Dent Res 2006;19:57-62.
    Abstract/FREE Full Text
  5. ↵
    1. Kerdpon D,
    2. Pongsiriwet S,
    3. Pangsomboon K,
    4. et al
    . Oral manifestations of HIV infection in relation to clinical and CD4 immunological status in northern and southern Thai patients. Oral Dis 2004;10:138-44.
    CrossRefMedlineWeb of Science
  6. ↵
    1. Coogan MM,
    2. Greenspan J,
    3. Challacombe SJ
    . Oral lesions in infection with human immunodeficiency virus. Bull World Health Organ 2005;83:700-6.
    MedlineWeb of Science
  7. ↵
    1. Ramírez-Amador V,
    2. Ponce-de-Leon S,
    3. Sierra-Madero J,
    4. Soto-Ramírez L,
    5. Esquivel-Pedraza l,
    6. Anaya-Saavedra G
    . Synchronous kinetics of CD4+ lymphocytes and viral load before the onset of oral candidosis and hairy leukoplakia in a cohort of Mexican HIV-infected patients. AIDS Res Hum Retroviruses 2005;21:981-90.
    CrossRefMedlineWeb of Science
  8. ↵
    1. Greenspan D,
    2. Gange SJ,
    3. Phelan JA,
    4. et al
    . Incidence of oral lesions in HIV-1-infected women: reduction with HAART. J Dent Res 2004;83:145-50.
    Abstract/FREE Full Text
  9. ↵
    1. Campo J,
    2. Del Romero J,
    3. Castilla J,
    4. García S,
    5. Rodríguez C,
    6. Bascones A
    . Oral candidiasis as a clinical marker related to viral load, CD4 lymphocyte count and CD4 lymphocyte percentage in HIV-infected patients. J Oral Pathol Med 2002;31:5-10.
    CrossRefMedlineWeb of Science
  10. ↵
    1. Ramirez-Amador V,
    2. Esquivel-Pedraza L,
    3. Sierra-Madero J,
    4. et al
    . Oral clinical markers and viral load in a prospective cohort of Mexican HIV-infected patients. AIDS 2001;15:1910-1.
    CrossRefMedlineWeb of Science
  11. ↵
    1. Patton LL,
    2. McKaig RG,
    3. Eron JJ Jr,
    4. Lawrence HP,
    5. Strauss RP
    . Oral hairy leukoplakia and oral candidiasis as predictors of HIV viral load. AIDS 1999;13:2174-6.
    CrossRefMedlineWeb of Science
  12. ↵
    1. EC-Clearinghouse on Oral Problems Related to HIV Infection World Health Organization Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus
    . Classification and diagnostic criteria for oral lesions in HIV infection. J Oral Pathol Med 1993;22:289-91.
    CrossRefMedlineWeb of Science
  13. ↵
    1. Flint SR,
    2. Tappuni A,
    3. Leigh J,
    4. Schmidt-Westhausen AM,
    5. MacPhail L
    . Markers of immunodeficiency and mechanism of HAART therapy on oral lesions. Adv Dent Res 2006;19:146-51.
    Abstract/FREE Full Text
  14. ↵
    1. Dunic I,
    2. Vesic S,
    3. Jevtovic DJ
    . Oral candidiasis and seborrheic dermatitis in HIV-infected patients on highly active antiretroviral therapy. HIV Med 2004;5:50-4.
    CrossRefMedlineWeb of Science
  15. ↵
    1. Ramírez-Amador V,
    2. Esquivel-Pedraza L,
    3. Sierra-Madero J,
    4. Anaya-Saavedra G,
    5. González-Ramírez I,
    6. Ponce-de-León S
    . The changing clinical spectrum of human immunodeficiency virus (HIV)-related oral lesions in 1,000 consecutive patients: a twelve-year study in a referral center in Mexico. Medicine 2003;82:39-50.
    CrossRefMedline
  16. ↵
    1. Skolasky Rl,
    2. Phair J,
    3. Detels R,
    4. Riddler S,
    5. Margolick J,
    6. Jacobson LP
    . Thrush and fever as markers of immune competence in the era of highly active antiretroviral therapy. AIDS Res Hum Retroviruses 2001;17:1311-6.
    CrossRefMedlineWeb of Science
  17. ↵
    1. Birnbaum W,
    2. Hodgson TA,
    3. Reichart PA,
    4. Sherson W,
    5. Nittayannanta SW,
    6. Axell TE
    . Prognostic significance of HIV-associated oral lesions and their relation with therapy. Oral Dis 2002;8:110-4.
    CrossRefMedlineWeb of Science
  18. ↵
    1. Greenspan JS,
    2. Greenspan D
    . The epidemiology of the oral lesions of HIV infection in the developed world. Oral Dis 2002;8:34-9.
    CrossRefMedlineWeb of Science
  19. ↵
    1. Greenspan JS
    . Sentinels and signposts: the epidemiology and significance of the oral manifestations of HIV disease. Oral Dis 1997;3(Suppl 1):13-7.
  20. ↵
    1. Miziara ID,
    2. Weber R
    . Oral candidosis and oral hairy leukoplakia as predictors of HAART failure in Brazilian HIV-infected patients. Oral Dis 2006;12:402-7.
    CrossRefMedlineWeb of Science
  21. ↵
    1. Patton LL
    . Sensitivity, specificity, and positive predictive value of oral opportunistic infections in adults with HIV/AIDS as markers of immune suppression and viral burden. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:182-8.
    MedlineWeb of Science
  22. ↵
    1. Gaitán-Cepeda LA,
    2. Martinez-Gonzalez M,
    3. Ceballos-Salobreña A
    . Oral candidosis as clinical marker of immune failure in patients with HIV/AIDS on HAART. AIDS Patient Care STDS 2005;19:70-7.
    CrossRefMedlineWeb of Science
  23. ↵
    1. Tappuni AR,
    2. Fleming GJP
    . The effect of antiretroviral therapy on the prevalence of oral manifestations in HIV-infected patients: a UK study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:623-8.
    CrossRefMedlineWeb of Science
  24. ↵
    1. Diz Dios P,
    2. Ocampo A,
    3. Miralles C,
    4. Limeres J,
    5. Tomás I
    . Changing prevalence of human immunodeficiency virus-associated oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:403-4.
    CrossRefMedlineWeb of Science
  25. ↵
    1. Etminan N
    . Pharmacoepidemiology II: the nested case-control study—a novel approach in pharmacoepidemiologic research. Pharmacotherapy 2004;24:1105-9.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Hulley SB,
    2. Cummings SR,
    3. Browner WS,
    4. Grady D,
    5. Hearst N,
    6. Newman TB
    . Designing clinical research. 2nd ed. Philadelphia: Lippincott Williams & Williams; 2001. p. 99-100.
  27. ↵
    1. Feinstein AR
    . Clinical epidemiology: the architecture of clinical research. Philadelphia: WB Saunders Company; 1985. p. 533-60.
  28. ↵
    1. Mercante DE,
    2. Leigh JE,
    3. Lilly EA,
    4. McNulty K,
    5. Fidel PL
    . Assessment of the association between HIV viral load and CD4 cell count on the occurrence of oropharyngeal candidiasis in HIV-infected patients. J Acquir Immune Defic Syndr 2006;42:578-83.
    CrossRefMedlineWeb of Science
  29. ↵
    1. Ohmit SE,
    2. Sobel JD,
    3. Schuman P,
    4. et al
    . Longitudinal study of mucosal Candida species colonization and candidiasis among human immunideficiency virus (HIV)-seropositive and at-risk HIV-seronegative women. J Infect Dis 2003;188:118-27.
    Abstract/FREE Full Text
  30. ↵
    1. Chattopadhyay A,
    2. Caplan DJ,
    3. Slade GD,
    4. Shugars DC,
    5. Tien H-C,
    6. Patton LL
    . Incidence of oral candidosis and oral hairy leukoplakia in HIV-infected adults in North Carolina. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:39-47.
    CrossRefMedlineWeb of Science
  31. ↵
    1. Chattopadhyay A,
    2. Caplan DJ,
    3. Slade DG,
    4. Shugars DC,
    5. Tien HC,
    6. Patton LL
    . Risk indicators for oral candidiasis and oral hairy leukoplakia in HIV-infected adults. Community Dent Oral Epidemiol 2005;33:35-44.
    CrossRefMedlineWeb of Science
  32. ↵
    1. Greenspan D,
    2. Komaroff E,
    3. Redford M,
    4. et al
    . Oral mucosal lesions and HIV viral load in the women's interagency HIV study (WIHS). J Acquir Immune Defic Syndr 2000;25:44-50.
    CrossRefMedlineWeb of Science
  33. ↵
    1. Margiotta V,
    2. Campisi G,
    3. Mancuso S
    . Plasma HIV-1 RNA and route of transmission in oral candidiasis and oral hairy leukoplakia. Oral Dis 2000;6:194-5.
    CrossRefMedlineWeb of Science
  34. ↵
    1. Margiotta V,
    2. Campisi G,
    3. Mancuso S,
    4. Accurso V,
    5. Abbadessa V
    . HIV infection: oral lesions, CD4+ cell count and viral load in an Italian study population. J Oral Pathol Med 1999;28:173-7.
    MedlineWeb of Science
  35. ↵
    1. Moura MD,
    2. Grossmann S de M,
    3. Fonseca LM,
    4. Senna MI,
    5. Mesquita RA
    . Risk factors for oral hairy leukoplakia in HIV-infected adults of Brazil. J Oral Pathol Med 2006;35:321-6.
    CrossRefMedlineWeb of Science
  36. ↵
    1. Rompalo AM,
    2. Astemborski J,
    3. Schoenbaum E,
    4. Schuman P
    . Comparison of clinical manifestations of HIV infection among women by risk group, CD4+ cell count, and HIV-1 plasma viral load. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:448-54.
    Medline
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  1. Clin Infect Dis. (2007) 45 (7): 925-932. doi: 10.1086/521251
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