Combined effects of HIV and obesity on the gastrointestinal microbiome of young men who have sex with men.

OBJECTIVES: The prevalence of obesity is rising among people living with HIV, which may synergistically increase inflammation and the risk of associated diseases. Disruption of gut bacterial communities may be one of the key drivers of this inflammation; however, the combined effects of HIV and obesity on the microbiome have not been explored. METHODS: This study included 381 men who have sex with men. Thirty-nine were HIV-positive and obese (H+O+), 143 were HIV-positive and nonobese, 64 were HIV-negative and obese, and 135 were HIV-negative and nonobese. Microbiome composition was assessed by targeted sequencing of the V4 region of the 16S ribosomal RNA (rRNA) gene using rectal swab samples. Inverse probability of treatment-weighted marginal structural models were used to investigate differences in microbial composition between groups while controlling for numerous clinical and behavioural confounders. RESULTS: Significant variability in microbial composition was explained by the combination of HIV and obesity, over and above each condition alone (R2 for the marginal contribution of the H+/O+ group = 0.008; P = 0.001). H+O+ participants had the highest ratios of Prevotella to Bacteroides, a pro-inflammatory enterotype that has been described in HIV infection and obesity independently. H+O+ participants had lower levels of Bacteroides and Veillonella than all other groups, suggesting a synergistic effect of HIV and obesity on these genera. CONCLUSIONS: Our findings support the hypothesis that HIV and obesity act together to disrupt gut microbial communities, which may help explain higher levels of generalized inflammation among people living with both HIV and obesity.

Prevalence of dementia after age 90: results from the 90+ study.

BACKGROUND: Although the prevalence of dementia increases with age from ages 65 to 85, whether this increase continues after age 90 is unclear. Most studies reporting on dementia prevalence do not have sufficient participants to estimate prevalence for specific ages and sexes above age 90. Here, we estimate age- and sex-specific prevalence of all-cause dementia in the oldest-old, those aged 90 and older. METHODS: Participants are 911 elderly from The 90+ Study, a population-based study of aging and dementia in people aged 90 and above. Dementia was diagnosed using in-person examinations as well as telephone and informant questionnaires. RESULTS: The overall prevalence of all-cause dementia was higher in women (45%, 95% CI = 41.5-49.0) than men (28%, 95% CI = 21.7-34.2). Among women, prevalence increased with age after age 90, essentially doubling every 5 years. A lower prevalence of dementia was significantly associated with higher education in women but not in men. CONCLUSIONS: In a very large sample of participants aged 90 and older, prevalence of all-cause dementia doubled every 5 years for women but not men.

Global effects estimation for multidimensional outcomes.

Many health studies focus on multifaceted outcomes that are not easily measured with a single variable; examples include studies on quality of life (QOL) and general health. To fully explore such an outcome, researchers typically collect information on multiple endpoints. The resulting measurements constitute multidimensional outcome data. An object of great interest is the overall-or global-effect of a covariate, such as a treatment intervention, on the multidimensional outcome. Quantifying such an effect can be difficult because multiple clinical outcomes are usually measured on different scales; the problem is enhanced by the fact that multiple measurements on a given subject are typically correlated. We present a regression modeling scheme permitting estimation of global treatment effects when multiple continuous endpoints are examined in concert either once or for several times. The global effect is conceptualized as a change in the distribution functions of the outcome variables. It may thus be interpreted as a connection between outcome distribution quantiles for the treatment and control groups. This concept allows the presentation of a global effect as a scalar quantity applicable to all outcomes simultaneously, easing interpretation of results. Model estimation proceeds directly from existing methods for multivariate survival analysis. The assumption that the treatment effect is homogenous across different outcomes is testable. To illustrate the application, we present data analytic results from a motivating example, an analysis of patients' QOL during recovery from lower limb trauma. We also explore the performance properties of global effects estimation through simulation.

Modeling Maternal-Infant HIV Transmission in the Presence of Breastfeeding with an Imperfect Test.

An important public health question is to determine the probabilities of perinatal HIV transmission and when it occurs, whether antepartum, intrapartum, or postpartum through breastfeeding. However, this is a difficult problem because the presence of HIV infection in an infant can only be ascertained through viral assays in the postpartum period. We propose a model that simultaneously estimates the risks of antepartum, intrapartum, and postpartum transmissions together with the sensitivity of the screening tests for HIV infection. The model allows estimating of infectivity through breast milk during postpartum periods. The methods are illustrated on a South African randomized clinical trial of extended AZT versus a short course of nevirapine in infants whose mothers had no access to antenatal antiretroviral therapy.

Calcium channel blockers and risk of AD: the Baltimore Longitudinal Study of Aging.

OBJECTIVE: To investigate the association between use of calcium channel blockers (CCB), dihydropyridine (DHP) or nondihydropyridine (nonDHP) type CCB and risk of developing Alzheimer's Disease (AD) or mortality. There is evidence suggesting that calcium plays a key role in changes in the brain leading to AD. Previous reports suggest a possible role for CCB in the treatment of AD. However, there are some indications that CCB increase mortality in patients with cardiac disease. METHODS: Subjects were 1092 participants in the Baltimore Longitudinal Study of Aging (BLSA) older than 60 years of age. Data on CCB use was collected prospectively for up to 19 years. Cox proportional hazards regression was used to estimate relative risks (RR) and confidence intervals (CI) of AD and mortality associated with use of CCB or use of only DHP or nonDHP-CCB. Analyses were adjusted for gender, education, smoking, blood pressure and history of heart problems. RESULTS: Use of DHP-CCB was not associated with a significantly reduced risk of AD compared to non-users, although the estimate of the RR was low with DHP-CCB (RR = 0.30, 95% CI = 0.07-1.25, P = 0.10). Use of nonDHP-CCB was not associated with reduced risk of AD and the estimate of the RR risk was close to one (RR = 0.82, 95% CI = 0.37-1.83, P = 0.63). In addition, there was no increase in mortality among users of DHP-CCB (RR = 0.64, 95% CI = 0.32-1.29, P = 0.21) or nonDHP-CCB (RR = 1.10, 95% CI = 0.65-1.87, P = 0.72). CONCLUSION: Users of DHP-CCB and nonDHP-CCB in this study did not have a significantly reduced risk of AD.

Visual memory predicts Alzheimer's disease more than a decade before diagnosis.

BACKGROUND: Recent studies have suggested that AD may reflect a chronic process that begins many years before the clinical expression of dementia. The current study examines premorbid Benton Visual Retention Test (BVRT) and Wechsler Adult Intelligence Scale-vocabulary (WAIS-voc) test scores in order to determine whether long-term deficits in these tests can predict the development of AD decades later in the Baltimore Longitudinal Study of Aging (BLSA). METHOD: Participants are volunteers from the BLSA, a multidisciplinary study of normal aging conducted by the National Institute on Aging. A total of 1,425 BLSA participants who were older than 60 years were included in the analyses. Cox proportional hazards models were used to estimate the relative risk of developing AD associated with BVRT and WAIS-voc scores at different time periods up to 20 years before the diagnosis of AD. RESULTS: The relative risks for 6 or more BVRT errors vs less than 6 errors at 1 to 3, 3 to 5, 5 to 10, and 10 to 15 years before the diagnosis of AD were 5.69, 2.11, 1.76, and 1.83 (p < 0.05). The relative risk for 15 or more years before diagnosis was not significant (p > 0.10). WAIS-voc scores were not significantly associated with the risk of AD in any time period. CONCLUSIONS: A greater number of errors on the BVRT is associated with an increased risk of AD up to 15 years later. Poor visual memory performance may represent an early expression of AD years before diagnosis. This result suggests the need to continue to revise views on the natural history of AD and the possibility of an increased window of opportunity for preventive treatment before definitive diagnosis.

Sensitivity and specificity of rapid HIV testing of pregnant women in India.

OBJECTIVE: Efforts to prevent HIV transmission from mother to infants in settings like India may benefit from the availability of reliable methods for rapid and simple HIV screening. Data from India on the reliability of rapid HIV test kits are limited and there are no data on the use of rapid HIV tests for screening of pregnant women. METHODS: Pregnant women attending an antenatal clinic and delivery room in Pune agreed to participate in an evaluation of five rapid HIV tests, including (a) a saliva brush test (Oraquick HIV-1/2, Orasure Technologies Inc.), (b) a rapid plasma test (Oraquick HIV-1/2) and (c) three rapid finger prick tests (Oraquick HIV-1/2; HIV-1/2 Determine, Abbott; NEVA HIV-1/2 Cadila). Results of the rapid tests were compared with three commercial plasma enzyme immunoassay (EIA) tests (Innotest HIV AB EIA, Lab systems/ELISCAN HIV AB EIA, UBI HIV Ab EIA). RESULTS: Between September 2000 and October 1, 2001, 1258 pregnant women were screened for HIV using these rapid tests. Forty-four (3.49%) of the specimens were HIV-antibody-positive by at least two plasma EIA tests. All of the rapid HIV tests demonstrated excellent specificity (96-100%). The sensitivity of the rapid tests ranged from 75-94%. The combined sensitivity and specificity of a two-step algorithm for rapid HIV testing was excellent for a number of combinations of the five rapid finger stick tests. CONCLUSION: In this relatively low HIV prevalence population of pregnant women in India, the sensitivity of the rapid HIV tests varied, when compared to a dual EIA algorithm. In general, the specificity of all the rapid tests was excellent, with very few false positive HIV tests. Based upon these data, two different rapid HIV tests for screening pregnant women in India would be highly sensitive, with excellent specificity to reliably prevent inappropriate use of antiretroviral therapy for prevention of vertical HIV transmission.

APOE genotype and survival in men and women with Alzheimer's disease.

BACKGROUND: The epsilon 4 allele of the APOE gene (APOE) is more frequent in patients with AD than in the general population, but studies are inconclusive as to whether it affects rate of progression or survival. Because survival in AD is generally longer in women than in men, the authors investigated whether APOE affects 10-year survival equally in men and women. METHODS: APOE testing was performed on 125 patients with probable AD enrolled in the Johns Hopkins AD Research Center between November 1984 and March 1987. The 39 men and 86 women were followed at 6-month intervals until censoring (by death or withdrawal from the study) or March 1997. Patients were dichotomized into those with and those without at least one epsilon 4 allele. For each sex, a Cox proportional hazards regression, allowing for delayed entry and covarying for age at onset, was used to examine the effect of epsilon 4 on survival. RESULTS: All patients who died during the study period and had autopsy (n = 92) were found to have definite AD. Average survival from disease onset did not differ by sex (12.1 years in men; 12.3 years in women). In neither sex were differences found between epsilon 4-positive and epsilon 4-negative subgroups in education, duration of AD at entry, or severity of dementia. However, in both sexes the epsilon 4-positive subgroup was approximately 3 years older at onset of AD and at entry to the study than the epsilon 4-negative subgroup. Adjusting for age at onset, the presence of an epsilon 4 allele significantly increased the relative risk of death only for men (RR = 2.69; 95% CI = 1.23 to 5.87). CONCLUSIONS: In this sample of mostly white, well-educated research participants with AD, the APOE epsilon 4 allele was associated with shorter survival in men but not in women.

Low carotenoid concentration and the risk of HIV seroconversion in Pune, India.

Low vitamin A and carotenoid levels could increase the risk of sexual HIV acquisition by altering the integrity of the genital epithelium or by immunologic dysfunction. We addressed this issue by measuring serum vitamin A and carotenoid levels in patients who were at risk of subsequent HIV infection. In a nested case-control study in individuals attending two sexually transmitted disease (STD) clinics in Pune, India, serum micronutrient levels were measured in 44 cases with documented HIV seroconversion (11 women and 33 men) and in STD patients matched for gender and length of follow-up with no subsequent HIV seroconversion (controls). STD patients in Pune had low vitamin A and carotenoid levels, and low serum beta-carotene levels were independently associated with an increased risk of subsequent HIV seroconversion. STD patients with beta-carotene levels less than 0.075 micromol/L were 21 times more likely to acquire HIV infection than those with higher levels (adjusted odds ratio = 21.1; p =.01). No such association was observed in case of other non-provitamin A carotenoids. This study reports the first evidence of an association between low serum provitamin A carotenoid levels and an increased risk for heterosexual HIV acquisition in STD patients in Pune, India.

Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda.

BACKGROUND: The probability of HIV-1 transmission per coital act in representative African populations is unknown. We aimed to calculate this probability overall, and to estimate how it is affected by various factors thought to influence infectivity. METHODS: 174 monogamous couples, in which one partner was HIV-1 positive, were retrospectively identified from a population cohort in Rakai, Uganda. Frequency of intercourse and reliability of reporting within couples was assessed prospectively. HIV-1 seroconversion was determined in the uninfected partners, and HIV-1 viral load was measured in the infected partners. Adjusted rate ratios of transmission per coital act were estimated by Poisson regression. Probabilities of transmission per act were estimated by log-log binomial regression for quartiles of age and HIV-1 viral load, and for symptoms or diagnoses of sexually transmitted diseases (STDs) in the HIV-1-infected partners. RESULTS: The mean frequency of intercourse was 8.9 per month, which declined with age and HIV-1 viral load. Members of couples reported similar frequencies of intercourse. The overall unadjusted probability of HIV-1 transmission per coital act was 0.0011 (95% CI 0.0008-0.0015). Transmission probabilities increased from 0.0001 per act at viral loads of less than 1700 copies/mL to 0.0023 per act at 38 500 copies/mL or more (p=0.002), and were 0.0041 with genital ulceration versus 0.0011 without (p=0.02). Transmission probabilities per act did not differ significantly by HIV-1 subtypes A and D, sex, STDs, or symptoms of discharge or dysuria in the HIV-1-positive partner. INTERPRETATION: Higher viral load and genital ulceration are the main determinants of HIV-1 transmission per coital act in this Ugandan population.

U.S. nephrologists' attitudes towards renal transplantation: results from a national survey.

BACKGROUND: Renal transplantation is the optimal treatment for persons with end-stage renal disease (ESRD). A shortage of kidneys in the U.S. has focused increasing attention on the process by which kidneys are allocated. A national survey was undertaken to determine the relative importance of both clinical and nonclinical factors in the recommendation for renal transplantation by U.S. nephrologists. METHODS: We conducted a national random survey of 271 U.S. nephrologists using hypothetical patient scenarios to determine their recommendation for renal transplantation based on demographic, clinical, and social factors. Specifically, eight unique patient scenarios were randomly distributed to each survey respondent. RESULTS: According to responding nephrologists (response rate 53%), females were less likely than males to be recommended for renal transplantation [adjusted odds ratio (OR)=0.41; confidence interval (CI) 0.21, 0.79; for whites]. Asian males were less likely than white males to be recommended for transplantation (OR=0.46, CI 0.24, 0.91). Black-white differences in rates of recommendation were not found. Other factors associated with low rates of recommendation for renal transplantation included history of noncompliance (OR=0.17, CI 0.13, 0.23), <25% cardiac ejection fraction (OR=0.15, CI 0.10, 0.21), HIV infection (OR=0.01, CI 0.00, 0.01), and being >200 lbs (OR=0.73, CI 0.56, 0.95). CONCLUSIONS: Female gender, and Asian but not black race, were associated with a decreased likelihood that nephrologists would recommend renal transplantation for patients with end stage renal disease. The well-documented black-white disparities in use of renal transplantation may be due to unaccounted for factors or may arise at a subsequent step in the transplantation process.

The statistical analysis of truncated data: application to the Sverdlovsk anthrax outbreak.

An outbreak of anthrax occurred in the city of Sverdlovsk in Russia in the spring of 1979. The outbreak was due to the inhalation of spores that were accidentally released from a military microbiology facility. In response to the outbreak a public health intervention was mounted that included distribution of antibiotics and vaccine. The objective of this paper is to develop and apply statistical methodology to analyse the Sverdlovsk outbreak, and in particular to estimate the incubation period of inhalational anthrax and the number of deaths that may have been prevented by the public health intervention. The data available for analysis from this common source epidemic are the incubation periods of reported deaths. The statistical problem is that incubation periods are truncated because some individuals may have had their deaths prevented by the public health interventions and thus are not included in the data. However, it is not known how many persons received the intervention or how efficacious was the intervention. A likelihood function is formulated that accounts for the effects of truncation. The likelihood is decomposed into a binomial likelihood with unknown sample size and a conditional likelihood for the incubation periods. The methods are extended to allow for a phase-in of the intervention over time. Assuming a lognormal model for the incubation period distribution, the median and mean incubation periods were estimated to be 11.0 and 14.2 days respectively. These estimates are longer than have been previously reported in the literature. The death toll from the Sverdlovsk anthrax outbreak could have been about 14% larger had there not been a public health intervention; however, the confidence intervals are wide (95% CI 0-61%). The sensitivity of the results to model assumptions and the parametric model for the incubation period distribution are investigated. The results are useful for determining how long antibiotic therapy should be continued in suspected anthrax cases and also for estimating the ultimate number of deaths in a new outbreak in the absence of any public health interventions.

Trends in crime and the introduction of a needle exchange program.

OBJECTIVES: This study sought to determine whether introduction of a needle exchange program would be associated with increased crime rates. METHODS: Trends in arrests were compared in program and nonprogram areas before and after introduction of a needle exchange program in Baltimore. Trends were modeled and compared via Poisson regression. RESULTS: No significant differences in arrest trends emerged. Over the study period, increases in category-specific arrests in program and nonprogram areas, respectively, were as follows: drug possession, 17.7% and 13.4%; economically motivated offenses, 0.0% and 20.7%; resistance to police authority, 0.0% and 5.3%; and violent offenses, 7.2% and 8.0%. CONCLUSIONS: The lack of association of overall and type-specific arrest data with program implementation argues against the role of needle exchange programs in increasing crime rates.

Feasibility of pooling sera for HIV-1 viral RNA to diagnose acute primary HIV-1 infection and estimate HIV incidence.

OBJECTIVE: To develop a pooling method for detection of viral RNA for diagnosis of acute HIV infection and estimation of HIV-1 incidence. METHODS: Sera from 700 consecutive seronegative patients attending sexually transmitted disease clinics in Pune, India, were screened individually for p24 antigen, and pooled into seven pools of 100 for detection of HIV-1 RNA by reverse transcriptase-polymerase chain reaction. HIV-1 incidence was calculated by the traditional cohort method, the p24 antigen method, and a multistage pooling method in which RNA-positive pools were re-analyzed in smaller pools. RESULTS: Sera from 700 individuals were grouped into seven pools of 100, of which four were positive. These four positive pools were subdivided into eight pools of 50, of which seven were positive. The seven positive pools were subdivided into 35 pools of 10, of which 10 were positive. Based on the 10 RNA-positive pools, the point estimate of HIV-1 incidence was 19.9% per year [95% confidence interval (CI), 7.3-31.8%]. Of the 700 samples analyzed for p24 antigen, eight were positive, resulting in a point estimate of incidence of 18.5%/year (8.0-36.5%). In contrast, the incidence rate based on the traditional cohort method of follow-up was lower at 9.4%/year (4.8-16.4%) due to a low follow-up rate. Testing of individual samples from the 10 RNA-positive pools identified 10 individuals with acute primary HIV-1. CONCLUSION: The multistage pooling method for detection of HIV-1 RNA was more sensitive than the p24 antigen method, and was five-fold less expensive than the p24 antigen assays. Pooling samples for RNA detection was effective in estimating current incidence rates with cost savings that would be practical for use in developing countries.

US nephrologists' recommendation of dialysis modality: results of a national survey.

Selection of a dialysis modality for persons with end-stage renal disease (ESRD) has important lifestyle and occupational implications. The factors affecting modality choice remain unclear, resulting in a low rate of peritoneal dialysis (PD) in the United States compared with other countries. A national survey of 271 US nephrologists was conducted from June 1997 to June 1998 to assess the relative importance of nonclinical and clinical factors related to dialysis modality selection for patients with ESRD. Hypothetical patient scenarios were randomly assigned to nephrologists to determine their recommendation for dialytic therapy based on patient demographic, clinical, and social factors. US nephrologists were more likely to recommend PD for men with ESRD compared with women (39% versus 33%; P: < 0.05; adjusted odds ratio, 1.44; 95% confidence interval, 1.15 to 1.80), as well as for patients with good compliance (adjusted odds ratio, 11.80; 95% confidence interval, 9.29 to 15.01), weight less than 200 lb (adjusted odds ratio, 2.3; 95% confidence interval, 1.8 to 2.9), residual renal function (adjusted odds ratio, 2.14; 95% confidence interval, 1.71 to 2.70), absence of diabetes (adjusted odds ratio, 2.0; 95% confidence interval, 1.6 to 2.5), and living with family (adjusted odds ratio, 1.7; 95% confidence interval, 1.4 to 2.1). Nephrologists in practice for 11 or more years were less likely to recommend PD. The association of male sex with PD therapy suggests a potential bias or sensitivity to women's perception of body image. Race was not associated with PD recommendations after controlling for other demographic and clinical characteristics. Because the incident US ESRD population is increasingly characterized by factors associated with not selecting PD (diabetes, obesity, malnourishment, living alone, and substance abuse problems), our results suggest that PD use may decrease over time.

Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging.

OBJECTIVE: To estimate age-specific incidence rates of AD in the Baltimore Longitudinal Study of Aging (BLSA). BACKGROUND: The BLSA is a volunteer cohort of normal subjects followed longitudinally with biennial evaluations at the Gerontology Research Center of the National Institute on Aging. METHODS: Subjects are 1236 participants (802 men, 434 women) in the BLSA with longitudinal follow-up between January 1985 and May 1998. The average length of follow-up was 7.5 years, with participants evaluated every 2 years by physical, neurologic, and neuropsychological examinations. Using Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, the authors diagnosed dementia and AD. RESULTS: The authors diagnosed 155 cases of dementia, of which 114 (74%) were AD. Incidence rates of AD increased with age from an estimated 0.08% per year (95% CI 0.00 to 0.43) in the 60 to 65 age group to an estimated 6.48% per year (95% CI 5.01 to 8.38) in the 85+ age group for men and women combined. The doubling time of incidence rates was estimated to be approximately 4.4 years and the median time of conversion from mild cognitive impairment to diagnosis of AD was estimated to be 4.4 years. There was a trend for women to have higher incidence rates than men and for fewer years of education to be associated with higher incidence rates; however, these effects were not significant. CONCLUSION: Incidence rates for AD in the BLSA are consistent with published rates in other studies. The longitudinally followed subjects of the BLSA offer a unique opportunity to prospectively investigate the antecedents of AD.

Methods for projecting the incidence and prevalence of chronic diseases in aging populations: application to Alzheimer's disease.

Projections of the incidence and prevalence of disease are important for public health planning. This paper describes methods for projecting the incidence and prevalence of a chronic disease in ageing populations. The approach uses age-specific disease incidence rates together with assumptions about survival to reconstruct disease prevalence. The methods can be used to evaluate the potential impact of public health interventions that may prevent disease or prolong survival. We used the methods to project the future prevalence of Alzheimer's disease in the United States. We found that the prevalence of Alzheimer's disease will nearly quadruple over the next 50 years. Although projections of the absolute prevalence are sensitive to assumptions about the age-specific incidence rates of disease, the proportionate growth is relatively insensitive. The increase in prevalence results from the ageing of the U.S. population. In order to perform the calculations, we have assembled U.S. Census population projections and U.S. mortality rates into computer software that is available from the authors at www.jhsph.edu/Departments/Biostats/software.h tml.

HIV-1-specific cytolytic T-lymphocyte activity correlates with lower viral load, higher CD4 count, and CD8+CD38-DR- phenotype: comparison of statistical methods for measurement.

OBJECTIVES: The objective of this study was to use novel statistical methods to determine the correlation between HIV-1-specific cytolytic T-lymphocyte (CTL) activity and HIV-1 plasma viral load, in a blinded study of HIV-infected patients at various stages of clinical disease. METHODS: Peripheral blood mononuclear cells (PBMC) were collected and stored at enrollment and 2 weeks later, from 15 HIV-infected individuals who were receiving stable antiretroviral therapy for the previous 6 weeks and during the study period. HIV-1-specific CTL activity was measured using an antigen-specific PBMC in vitro stimulation method. Measurements of plasma viral load, as well as CD4+ and CD8+ T lymphocytes expressing T-cell activation markers (DR and CD38) were also performed at each time point. CTL activity was quantified using three separate statistical methods: area under the net HIV-specific lysis curve (AUC), lytic units (LU20), and linear regression (LR) of net HIV-specific lysis. RESULTS: HIV-1 nef-, pol- and gag-specific CTL activity (AUC method) was significantly higher in subjects with a plasma viral load < or = 30,000 RNA copies/ml, than in those with viral load >30,000 RNA copies/ml. When plasma viral load was analyzed as a continuous variable, there was a strong correlation between higher CTL activity and lower viral load for nef (r2 = .77; p < .001), pol (r2 = .63; p < .001) and gag (r2 = 0.75; p < .001) targets by the AUC, but not for the LU20 analysis. Using the LR analysis, which is less dependent on in vitro PBMC growth than the AUC analysis, an independent association was demonstrated between nef- and gag-specific CTL activity and lower viral load. Measurement of CTL activity was also significantly correlated with a higher percentage of circulating CD8+DR-CD38- T lymphocytes. CONCLUSIONS: In this blinded study using an in vitro stimulation of frozen PBMC, higher HIV-1 nef-, pol-, and gag-specific CTL activity correlated with lower plasma viral load, particularly in patients with a CD4 count <500 cells/mm3. Two new statistical methods for estimating CTL activity, AUC and LR analyses, were superior to the standard lytic unit (LU20) method for demonstrating this correlation. These data also demonstrated that higher circulating CD8+ T lymphocytes with a DR-CD38-phenotype, correlate with a lower plasma viral and load and higher HIV-specific CTL activity. This suggests that lymphocytes with this double-negative phenotype may include circulating HIV-specific CD8+ CTL.

Application of random effects models and other methods to the analysis of multidimensional quality of life data in an AIDS clinical trial.

BACKGROUND: Current analytic methods applied to multidimensional health-related quality of life (HRQOL) data do not borrow strength across analyses and do not produce summary estimates of effect. OBJECTIVES: To compare a random effects modelling approach for the analysis of multidimensional HRQOL data to the following: (1) separate analyses for each dimension; (2) O'Brien's global test procedure; and (3) multivariate analysis of variance (MANOVA). RESEARCH DESIGN: Randomized clinical trial comparing 3 treatments (Trimethoprim-Sulfamethoxazole [TS], Dapsone-Trimethoprim [DT], and Clindamycin-Primaquine [CP] for Pneumocystis carinii pneumonia [PCP]). SUBJECTS: Patients with PCP enrolled in AIDS Clinical Trials Group Protocol 108. MEASURES: A 33-item battery assessing 7 dimensions of HRQOL: physical functioning, pain, energy, general health perceptions, disability, pulmonary symptoms, and constitutional symptoms. RESULTS: Analyses focused on changes in score from baseline to Day 7 (n = 145). Separate analyses for each dimension suggested a trend favoring CP versus TS, but using a Bonferroni correction no differences were statistically significant. O'Brien's global procedure for a test of no-treatment effect versus superiority of one treatment yielded P = 0.07. MANOVA did not reveal significant differences among treatment groups. A random effects model using fixed treatment and dimension effects and separate random effects for each person showed a significant overall treatment effect (P = 0.02); changes in scores for CP averaged 10 points greater than for TS. CONCLUSIONS: Random-effects models provide a flexible class of models for analyzing multidimensional quality of life data and estimating treatment effects because they borrow strength across dimensions.