Relationship between Pharmacokinetics and Pharmacodynamic Responses in Healthy Smokers Informs a Once-Daily Dosing Regimen for Nemiralisib.

Nemiralisib (GSK2269557), a potent inhaled inhibitor of phosphoinositide 3-kinase δ (PI3Kδ), is being developed for the treatment of respiratory disorders including chronic obstructive pulmonary disease. Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers (n = 56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1-6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-(4,5)-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% confidence interval [CI], 11%-34%) and 36% (90% CI, 11%-64%) after a single dose or after 14 days of treatment with nemiralisib, respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ∼3- to 4.5-fold (peak vs. trough) in plasma exposure after 14 days of nemiralisib treatment. The BAL analysis at trough confirmed higher levels of the drug in the lungs versus plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). A comparison of the drug levels in plasma and the reductions in sputum PIP3 showed a direct relationship between exposure and PIP3 reduction. These results demonstrated target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen.

Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD.

BACKGROUND: While current therapies reduce symptoms in chronic obstructive pulmonary disease (COPD) patients, substantial unmet need remains and novel treatments are highly desired. Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase specifically expressed in leucocytes and involved in their recruitment and activation. This study evaluated the safety, pharmacokinetics (PK) and dose-response characteristics of inhaled GSK2269557, a PI3Kδ inhibitor, in moderate-to-severe COPD patients with stable disease. METHODS: In this randomised, double-blind, placebo controlled, parallel group study, patients received once daily inhaled treatment with GSK2269557 1000 µg or placebo for 14 days (Part A, primary aim safety, N = 28 patients). In part B of the study (primary aim pharmacodynamic dose-response, N = 36 patients), GSK2269557 100, 200, 500, 700, 1000, 2000 µg or placebo was given for 14 days. In both Part A and B, GSK2269557 was added to the usual maintenance therapy. Safety, PK assessments and induced sputum collection for cytokine analysis were conducted at baseline and after 7 and 14 days of treatment. Adverse events (AEs) were monitored throughout. RESULTS: In Part A, mean age was 61.7 years (SD 6.7), 29% were females, and mean FEV1% predicted was 59.7% (SD 11.4)2. In Part B, mean age was 63.3 years (SD 6.3), 44% were females, and mean FEV1% predicted was 56.5% (SD 11.5)2. GSK2269557 was well tolerated in both parts of the study; the most commonly reported AEs were cough and headache, with cough being reported with a greater incidence in the GSK2269557 groups vs. placebo (Part A: 19% vs. 14% and Part B: range of 0-80% for different doses vs. 0% on placebo). No drug-related serious AEs or clinically significant changes in any other safety parameters were reported. GSK2269557 was rapidly absorbed into plasma following all doses with a maximum peak at approximately 2 h. Following repeat administration, accumulation in plasma was approximately 2-3 fold from Day 1 to Day 7. At Day 14, relative to placebo, sputum interleukin (IL)-8 and IL-6 levels were reduced on average by 32% and 29% respectively after inhalation of GSK2269557 1000 µg in Part A. In Part B, although inhibition of both IL-8 and IL-6 levels was observed, the levels were variable and there was insufficient evidence to support a monotonic dose-response. CONCLUSIONS: In this study, inhaled GSK2269557 had an acceptable safety profile for progression into larger studies in COPD patients. Moreover, inhalation of GSK2269557 resulted in suppression of sputum IL-8 and IL-6 levels, consistent with the known anti-inflammatory activity of a PI3Kδ inhibitor. Inhibition of inflammatory cytokines in the airway compartment may contribute to the potential therapeutic benefit of a PI3Kδ inhibitor in chronically inflamed COPD patients.

Primary total hip replacement in childhood, adolescence and young patients: quality and outcome of clinical studies.

OBJECTIVE: The present meta-analysis illustrates relevant information about hip replacement in young patients that has been published during the past 3 decades. MATERIAL AND METHODS: Based on a MedLine literature review a total of 95 studies were evaluated. Parameters for evaluation of study quality and outcome were implant survival rates (ISR),number of patients, indications, follow-up, surgical approaches and number of surgeons. RESULTS: Most studies consider patient numbers <50. In 33 studies one implant system was applied compared to 65 studies in which more than one system was used. Most studies include different surgical approaches. 20% of all studies contained neither the number of surgeons,nor the type of surgical approach. The overall ISR could be evaluated in 67 studies. Sufficient data about the ISR of stem and/or sockets were available in 50 papers. CONCLUSIONS: Most published studies analyzed inhomogeneous study populations; study variables vary as do the implants used for treatment.

Analysis of multiple 2x2 tables with site-specific periodontal data.

Periodontal data typically consist of observations made at multiple sites within each patient. Observations within a patient tend to be positively correlated; hence, standard statistical techniques that assume independence are invalid. Regression techniques for correlated data have been proposed; communicating results from these models, however, is difficult, due to their inherent complexity. Simpler statistical approaches have also been proposed, but many of these methods can be applied only when covariates are specific to the subject, and do not vary from site to site within a subject. In this paper, we present two methods for the analysis of multiple 2x2 tables containing site-specific periodontal data. The methods presented are modifications of the well-known Mantel-Haenszel methods. We illustrate these methods using a subset of data from a clinical trial examining the effects of scaling and root planing on levels of interleukin-1 beta.

Modulation of the release of endogenous adenosine by cannabinoids in the myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum.

1. Interactions between the cannabinoid system and the adenosine system were investigated in the myenteric plexus-longitudinal muscle (MPLM) of the guinea-pig ileum. 2. Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by exogenous adenosine and the adenosine receptor agonist 2-chloroadenosine. These inhibitory effects were reversed by the selective A(1) receptor antagonist DPCPX (20 nM). 3. Preincubation of the MPLM with the cannabinoid receptor agonist CP55,940 (1 nM) or the endogenous cannabinoid ligand anandamide caused a significant leftward shift in the concentration-effect curves to adenosine and 2-chloroadenosine. 4. Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by the adenosine uptake inhibitor dipyridamole. This inhibition was reversed by DPCPX (20 nM). 5. Pretreatment with CP55,940 (1 nM) or anandamide (10 microM) significantly reduced the inhibition produced by dipyridamole, an effect which was completely reversed by the selective CB(1) receptor ligand SR141716 (100 nM). 6. Electrically evoked adenosine release, measured in real time by means of adenosine-specific biosensors, was inhibited by CP55,940 (10 nM). This inhibition was blocked when CP55,940 was applied in the presence of SR141716 (100 nM). 7. These results confirm the presence of presynaptic CB(1) and A(1) receptors in the guinea-pig MPLM, and suggest that CB(1) receptor stimulation reduces electrically-evoked adenosine release. Overall the data raise the possibility that the cannabinoid system plays a role in the modulation of adenosine transmission in the MPLM.

Influence of variation in birth weight within normal range and within sibships on IQ at age 7 years: cohort study.

OBJECTIVE: To examine the relation between birth weight and measured intelligence at age 7 years in children within the normal range of birth weight and in siblings. DESIGN: Cohort study of siblings of the same sex. SETTING: 12 cities in the United States. SUBJECTS: 3484 children of 1683 mothers in a birth cohort study during the years 1959 through 1966. The sample was restricted to children born at >/=37 weeks gestation and with birth weights of 1500-3999 g. MAIN OUTCOME MEASURE: Full scale IQ at age 7 years. RESULTS: Mean IQ increased monotonically with birth weight in both sexes across the range of birth weight in a linear regression analysis of one randomly selected sibling per family (n= 1683) with adjustment for maternal age, race, education, socioeconomic status, and birth order. Within same sex sibling pairs, differences in birth weight were directly associated with differences in IQ in boys (812 pairs, predicted IQ difference per 100 g change in birth weight =0.50, 95% confidence interval 0.28 to 0.71) but not girls (871 pairs, 0.10, -0.09 to 0.30). The effect in boys remained after differences in birth order, maternal smoking, and head circumference were adjusted for and in an analysis restricted to children with birth weight >/= 2500 g. CONCLUSION: The increase in childhood IQ with birth weight continues well into the normal birth weight range. For boys this relation holds within same sex sibships and therefore cannot be explained by confounding from family social environment.

Observations on patellar height following opening wedge proximal tibial osteotomy.

Patellar height and patellar ligament length were assessed pre- and postoperatively in 28 patients who underwent a medial opening wedge proximal tibial osteotomy for varus gonarthrosis. This procedure produced no significant change in patellar ligament length. Pre- and postoperative Insall-Salvati ratios were 0.96+/-0.12 and 0.97+/-0.15, respectively (P=.30). The Insall-Salvati ratio decreased in 29% of patients, and no patient experienced a decline >0.07. The distance between the patella and tibiofemoral joint line ("patellar height") decreased in 100% of patients. The mean Blackburne-Peel ratio declined from 0.75+/-0.13 to 0.53+/-0.15 (P<.001). Sixty-four percent of the postoperative Blackburne-Peel values satisfied the radiographic criterion for patella infera (Blackburne-Peel ratio <0.54). Whereas the loss of patellar height, historically associated with lateral closing wedge proximal tibial osteotomy, is a function of patellar ligament contracture, the decreased distance between the patella and the tibiofemoral joint line following medial opening wedge proximal tibial osteotomy is a function of joint line elevation. The high incidence of patella infera following medial opening wedge proximal tibial osteotomy may have deleterious effects on patellofemoral biomechanics or may complicate subsequent total knee arthroplasty.

Signal transduction of cannabinoid CB1 receptors in a smooth muscle cell line.

1. The effects of cannabinoid (CB) receptor stimulation on membrane currents in single cells from the Syrian hamster vas deferens cell line DDT1MF-2 were investigated using the whole cell patch clamp technique. 2. The CB receptor agonist CP55,940 evoked a concentration-dependent transient outward current. The selective CB1 receptor ligand SR141716 (1 microM), but not the selective CB2 receptor ligand SR144528 (1 microM), inhibited the outward current. Pertussis toxin (100 ng ml-1 for 20 h) completely abolished the outward current. 3. Western blotting with an antibody against the rat (r)CB1 receptor showed a band characteristic for the CB1 receptor around 63 kDa in DDT1MF-2 cells. 4. The reversal potential for the outward current measured using a voltage ramp protocol was -84 +/- 5 mV. The current was inhibited by the Ca2+-dependent K+ channel blockers iberiotoxin (10 nM) and charybdotoxin (10 nM). 5. Removal of Ca2+ from the bathing solution, or the addition of 0.1 mM Cd2+ completely abolished the outward current evoked by 10 microM CP55,940. 6. The sarcoplasmic Ca2+ pump inhibitor thapsigargin reduced the outward current evoked by 10 microM CP55,940 in a concentration-dependent manner. 7. The mitogen-activating protein kinase (MAP kinase) inhibitor PD98059, but not the phospholipase C inhibitor U73122, inhibited the outward current evoked by 10 microM CP55,940. 8. The adenylyl cyclase inhibitor SQ22,536 (100 microM) and 8-Br-cyclic AMP (10 microM) significantly reduced the outward current evoked by 10 microM CP55,940. 9. Our data suggest that CB1 receptor stimulation in DDT1MF-2 cells leads to activation of a large conductance Ca2+-dependent K+ channel through a Gi/Go protein-mediated rise in [Ca2+]i, for which both inhibition of adenylyl cyclase and activation of MAP kinase are required. In addition, the cannabinoid-induced increase in [Ca2+]i is likely to arise from capacitive Ca2+ entry.

The design of the prenatal determinants of schizophrenia study.

This paper describes the Prenatal Determinants of Schizophrenia (PDS) Study; three companion papers report the first results. The PDS Study was designed to study early antecedents of schizophrenia in a birth cohort of 1959-1967 for whom a wealth of archived prenatal data--including maternal sera--was available. Making use of the registries of a health plan into which the cohort was born, we ascertained and then diagnosed 71 cases of schizophrenia and spectrum disorders in the cohort. We describe herein the available prenatal data, the process of case diagnosis, and the strategies used to analyze prenatal determinants of schizophrenia in this cohort. Data are presented that bear on the main sources of potential bias and are important to understanding the strengths and limitations of this unique data set.

Maternal prepregnant body mass and risk of schizophrenia in adult offspring.

This study examined the relation between maternal prepregnant body mass index (BMI) and development of schizophrenia and schizophrenia spectrum disorders in adult offspring from the Prenatal Determinants of Schizophrenia Study. The study drew on a previously studied cohort of births occurring between 1959 and 1967 to women enrolled in a prepaid health plan. Computerized treatment registries were used to identify possible cases of schizophrenia and spectrum disorders in adult offspring belonging to the health plan from 1981 to 1997. Diagnostic interviews and medical record reviews resulted in diagnosis of 63 cases of schizophrenia and spectrum disorders; these cases and 6,570 unrelated and unaffected cohort members whose mothers also had prepregnancy measures of BMI comprised the sample for analyses. High (> or = 30.0), compared with average (20.0-26.9), maternal prepregnant BMI (kg/m2) was significantly associated with schizophrenia and spectrum disorders in the adult offspring (relative risk [RR] = 2.9; 95% confidence interval [CI] 1.3-6.6), independently of maternal age, parity, race, education, or cigarette smoking during pregnancy. Low (< or = 19.9) maternal BMI was not associated with schizophrenia and spectrum disorders (RR = 1.2; 95% CI 0.64-2.2). Future studies of this cohort will examine factors that may help explain the relationship of high maternal prepregnant BMI with schizophrenia, including nutritional and metabolic factors, toxic exposures, and obstetrical complications.

Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study.

We sought to examine the relationship between maternal exposure to adult respiratory infections and schizophrenia spectrum disorder (SSD) in the Prenatal Determinants of Schizophrenia (PDS) Study, a large birth cohort investigation. Previous work suggests that second trimester exposure to respiratory infection may be a risk factor for SSD. We therefore examined whether this class of infection was associated with adult SSD. For this purpose, we capitalized on several design advantages of the PDS Study, including a comprehensive, prospective data base on physician-diagnosed infections and a continuous followup in which diagnoses of SSD were made, in the majority, by face-to-face interview. Second trimester exposure to respiratory infections was associated with a significantly increased risk of SSD, adjusting for maternal smoking, education, and race (rate ratio [RR] = 2.13 [1.05-4.35], chi2 = 4.36, df= 1,p = 0.04); no associations were shown for first trimester and third trimester exposure to these respiratory infections. These findings support-and extend-previous studies suggesting that second trimester respiratory infections are risk factors for SSD. This study therefore has implications toward uncovering the etiology of schizophrenia and developing preventive strategies.

Incidence and cumulative risk of treated schizophrenia in the prenatal determinants of schizophrenia study.

The present study uses data from the Prenatal Determinants of Schizophrenia (PDS) Study to derive age- and sex-specific estimates of incidence and cumulative risk for DSM-IV schizophrenia. Although not designed as an incidence study, the PDS Study uses both a well-defined population under continuous followup and DSM-IV diagnoses. The originating cohort was established in Alameda County, California, during 1959-1967 and yielded 12,094 cohort members followed from 1981 to 1997 during the principal ages at risk for schizophrenia. Survival analytic techniques showed that schizophrenia incidence rates per 10,000 person-years for men were 9.4 for ages 15-19; 5.6 for ages 20-24; 3.3 for ages 25-29; and 0.9 for ages 30-34. Schizophrenia incidence rates per 10,000 person-years for women were 1.6 for ages 15-19; 1.3 for ages 20-24; and 4.1 for ages 25-29. The cumulative risk for schizophrenia by age 38 was 0.93 percent for men and 0.35 percent for women. These estimates of incidence rates and risk were higher than those in traditional incidence studies but similar to recent findings in other cohorts. Possible explanations for the apparently high rates of disorder include chance, design effects, and true variation in risk over time and place.

Effects of a 6-month vitamin intervention on DNA damage in heavy smokers.

Because their formation is associated with tumor development in specific tissues, DNA adducts have potential usefulness as intermediate end points in chemoprevention studies. To determine the efficacy of a combination of antioxidant vitamins (vitamins C and E and beta-carotene), a randomized clinical trial was conducted among heavy smokers using DNA damage as the end point. Immunological methods were used to measure polycyclic aromatic hydrocarbon-DNA adducts and oxidative DNA damage (8-oxo or hydroxydeoxyguanosine) in mononuclear and oral cells. A total of 121 subjects were randomized to the 6-month intervention and received either vitamins or placebo. Dropout rates were higher in the placebo than in the vitamin group; 65% of subjects in the vitamin group, but only 47% in the placebo group, provided specimens at 6 months. Plasma levels of all three antioxidants rose significantly in the vitamin group but not in the placebo group. All four measures of DNA damage decreased in both groups; the between-group differences were not statistically significant. These data do not provide clear evidence that antioxidant vitamin intake prevents DNA damage. However, the study demonstrates that DNA damage is a useful end point in chemoprevention trials.

Interval estimation of the common odds ratio from k(2 x 2) tables under cluster sampling.

We propose a simple correction factor for the variance of the logarithm of the common odds ratio estimated by the method of Mantel and Haenszel from a series of (2 x 2) tables when data are cluster correlated. The adjustment is applied to the variance estimators proposed by Hauck and by Robins, Breslow and Greenland for the log of the Mantel-Haenszel common odds ratio, and its performance is evaluated in a simulation study. The key features of the proposed adjustment are: (i) it has closed-form; (ii) it can accommodate covariates defined at the cluster-specific level, the site-specific level, or both; and (iii) it does not require the user to specify a particular correlation structure for the response data. The correction derives from Liang and Zeger's generalized estimating equations (GEE) technique for logistic regression modelling. Via simulation, we examine empirical versus nominal coverage probabilities for interval estimation of the common odds ratio using adjusted and unadjusted variance estimates, and we present ratios of observed to estimated variances. Results are compared to those obtained from the fully iterated GEE analysis. The characteristics of the simulation study mimic scenarios common in the periodontal research setting, with small numbers of subjects (N = 25, 50), moderate numbers of sites per cluster (m = 4, 16, 32), and modest intracluster correlation levels (rho = 0.0, 0.1, 0.2, 0.3). Results show that adjusted confidence intervals (applied to the Hauck or the Robins, Breslow, Greenland variance estimate) provide coverage probabilities close to the nominal level for the Mantel--Haenszel common odds ratio over a variety of cluster sizes and levels of correlation.

Analyzing k (2 x 2) tables under cluster sampling.

In many data analytic applications, such as ophthalmologic, longitudinal, or periodontal studies, multiple observations are recorded over several sites (or timepoints) within the same subject, bringing about dependence between measurements. This correlation, in turn, precludes the use of standard statistical methods that assume independence between outcome measurements. For example, the Mantel-Haenszel statistic, used to assess association between a binary outcome and a binary exposure while adjusting for a categorical covariate, does not follow the usual chi-squared distribution under the null hypothesis when there is correlation between observations. A modified Mantel-Haenszel procedure, which makes adjustment for dependence, is proposed. No particular correlation structure is assumed for responses within a cluster. This closed-form adjustment stems from Liang and Zeger's (1986, Biometrika 73, 13-22) generalized estimating equations approach for clustered data. The difference between this tabular (i.e., noniterative) technique and many earlier tabular methods is that the current method allows for consideration of site-specific exposure and covariate information. An example from a periodontal research study illustrates application of the method.

New concepts regarding the pathogenesis of periodontal disease in HIV infection.

Periodontal manifestations of human immunodeficiency virus (HIV) infection were first described in 1987. Initially, the lesions receiving attention were HIV-associated gingivitis (now known as linear gingival erythema [LGE]) and HIV-associated periodontitis (now known as necrotizing ulcerative periodontitis [NUP]). The true prevalence of LGE was difficult to determine due to variable diagnostic criteria. Recently, LGE has been associated with intraoral Candida infection. The prevalence of NUP is low (< or = 5%), and this lesion is associated with pronounced immunosuppression. Current focus on the periodontal manifestations of HIV infection centers on rapid progression of chronic adult periodontitis in HIV+ patients. Attempts to identify the pathogenesis of the increased progression of periodontitis have not proven successful. For example, analysis of subgingival plaque for the presence of bacterial pathogens has failed to detect differences between HIV+ and HIV- patients. Recently our laboratory has identified alterations in the host response in the gingival crevice of HIV+ patients. Comparing HIV+ and HIV- injecting drug users (IDU), levels of the proinflammatory cytokine interleukin-1 beta (IL-1 beta) in gingival crevicular fluid (GCF) were slightly elevated at sites with a probing depth of 1 to 3 mm. At deeper sites (> or = 4 mm), total IL-1 beta in GCF was significantly greater in HIV+ individuals. Using the lysosomal acid glycohydrolase beta-glucuronidase (beta G) as a measure of the influx of polymorphonuclear leukocytes (PMN) into the gingival crevice, our data indicated a significant correlation of total beta G in GCF and probing depth in the HIV-IDU (r = 76; P = .02). This result was similar to what we have observed in other studies. In contrast, for HIV+ subjects, total beta G was not associated with probing depth (r = .20; NS). These data suggest that HIV+ patients have altered regulation of PMN recruitment into the gingival crevice. We have begun to investigate the conditions under which subgingival Candida may contribute total periodontal lesions in HIV+ individuals. Candida from subgingival sites has been cultured in HIV+ individuals. Subgingival Candida was distinct from Candida isolated from tongue and buccal mucosal surfaces (as indicated by genomic fingerprinting). We hypothesize the absence of adequate priming of PMN by HIV+ patients. This may be due to a reduced Th1 lymphocyte response. The inability of HIV+ individuals to adequately prime PMN may allow Candida to colonize the subgingival environment. In that milieu, it may act directly or in concert with subgingival bacterial pathogens, or as a cofactor (by inducing production of proinflammatory cytokines) to increase the occurrence of periodontal attachment loss.

Re-examining the role of prostate-specific antigen density in predicting outcome for clinically localized prostate cancer.

OBJECTIVES: To evaluate the prognostic significance of prostate-specific antigen density (PSAD) in clinically localized prostate cancer and determine whether this index is independent of or superior to prostate-specific antigen (PSA) in predicting outcome of patients treated with external beam radiotherapy. METHODS: Between January 1989 and December 1993, 175 evaluable patients with clinically localized prostate cancer received definitive radiotherapy using computed tomography (CT)-guided conformal techniques. PSAD was defined as the ratio of the pretreatment serum PSA to the prostate volume measured from CT treatment planning scans by one investigator. All PSA values were determined using the Hybritech assay. Biochemical failure was defined as two consecutive elevations in PSA separated by at least 3 months and a final PSA value greater than 1 ng/mL. RESULTS: Multivariate analysis including PSA and Gleason score revealed both to be statistically significant predictors of biochemical disease-free survival (P = 0.048 and P < 0.001, respectively). PSAD did not achieve significance on regression analysis. A direct multivariate analysis including PSA and PSAD required dichotomization in order to reduce high correlation. This analysis demonstrated a relative risk (RR) for failure of 1.27 (NS) for high PSA versus low PSA compared with a RR of 1.20 (NS) for high PSAD versus low PSAD. A regression model containing all three variables indicated only the Gleason score as significant in predicting biochemical failure. CONCLUSIONS: These data do not suggest that PSAD is either an independent prognostic factor or a stronger discriminant of outcome than PSA in patients with clinically localized prostate cancer treated with definitive external beam radiotherapy. Larger patient numbers with longer follow-up data, use of a clinical end point, or an analysis restricted to the appropriate subgroup may demonstrate the utility of PSAD in the future.

Oral candidiasis in HIV infection: predictive value and comparison of findings in injecting drug users and homosexual men.

The objectives of this study were to compare the relationship of oral candidiasis to HIV status, cohort and CD4+ lymphocyte values in injecting drug users and homosexual men and to examine its impact on prognosis. An oral examination was added to an ongoing longitudinal study of HIV infection. Data obtained at 6-month intervals included smoking, illicit drug use, medication use, symptoms and medical diagnoses, physical examination findings and laboratory data. In this study HIV+ subjects were much more likely to present with oral candidiasis than were HIV- subjects (OR = 6.3, P < 0.01). Injecting drug users, regardless of serostatus, were more likely than homosexual men to present with oral candidiasis (OR = 3.0, P = 0.001). In both cohorts oral candidiasis was associated with low CD4+ lymphocyte counts and percent ages, and Kaplan-Meier survival estimates showed that subjects with oral candidiasis had a poorer prognosis than those without candidiasis, even after controlling for CD4+ lymphocyte count.

A prospective study of oral lesions and their predictive value for progression of HIV disease.

OBJECTIVE: This report evaluates and compares individual oral lesions and combinations of lesions in predicting progression-free survival in a seroprevalent cohort of men and women with HIV infection. DESIGN: This was a prospective study of HIV-infected patients, initially AIDS-free, followed for approximately 30 months. SETTING: Patients were volunteers examined at an academic medical center and at an inner-city hospital in New York. Participants identified themselves as homosexual men or as injection drug users (IDU). OUTCOME MEASURES: The primary outcome being assessed is time from a baseline oral examination until the development of an AIDS-defining condition or death from any cause within 12 months of the last study visit. Correlation is measured by relative risk (RR). RESULTS: While oral lesions were not predictive of progression among subjects with CD4 > or = 200, they were highly predictive of progression among those with CD4 < 200. For subjects with CD4 < 200, the only individual lesion that was significantly associated with progression-free survival was oral candidiasis (RR = 4.12, P = 0.009). Positivity for one or more lesions in a set demonstrated greater prognostic value among those with CD4 < 200, with RR's of 6.03 (P = 0.018) for the set consisting of oral candidiasis, hairy leukoplakia, and necrotizing ulcerative gingivitis (NUG), and 8.77 (P = 0.036) for the set consisting of the above lesions plus linear gingival erythema (LGE). Analysis by cohort suggested that the improvement in correlation was stronger in homosexual men than in IDU, but this question could not be resolved conclusively with these data. CONCLUSIONS: Lesion sets might be better prognosticators of progression-free survival than individual lesions among HIV-infected subjects with CD4 < 200. Prognostic value of the core lesion set (oral candidiasis and hairy leukoplakia) was enhanced by the addition of other lesions (NUG and LGE) not usually included in HIV staging systems. These results suggest that staging systems for HIV might be improved by the inclusion of other, survival-related oral lesions.