Biomedical subjects

Joseph B Margolick

Publications and source records attributed to Joseph B Margolick.

At least 19 recordsLinked to original sources

PubMed2026

Human Immunodeficiency Virus-Associated Proteomic Signature of Myocardial Fibrosis and Incident Heart Failure.

BACKGROUND: People with human immunodeficiency virus (HIV) (PWH) are at higher risk of myocardial fibrosis and subsequent heart failure (HF) compared to people without HIV (PWOH). Mechanisms underlying this risk and its specificity to PWH are unclear. METHODS: We measured 2594 proteins in plasma obtained concurrently with cardiovascular magnetic resonance imaging among 342 PWH and PWOH. We estimated associations with HIV serostatus and myocardial fibrosis (elevated extracellular volume fraction [ECV] ≥30% among women, ≥28% among men) using multivariable regression. Among an independent community-based cohort, we estimated associations between the identified signature and time to incident HF. RESULTS: Mean age of participants was 55 (standard deviation [SD], 6) years, 25% were female, 61% were PWH (88% on antiretroviral therapy, 74% with undetectable HIV RNA), and 52% had elevated ECV. We identified 39 proteins and 1 cluster of 42 proteins that were higher among PWH versus PWOH and positively associated with elevated ECV, independent of risk factors (false discovery rate <0.05). Among an independent cohort of 3223 PWOH (mean age, 68 [SD, 9] years; 52% female; 118 incident HF cases over a mean of 9.8 [SD, 1.4] years), we found that this protein cluster and 34 of 39 individual proteins were associated with time to incident HF. This signature was statistically enriched for T-cell activation, tumor necrosis factor signaling, ephrin signaling, and tissue maintenance and repair. CONCLUSIONS: We identified an HIV-related proteomic signature associated with myocardial fibrosis regardless of HIV serostatus and that predicted incident HF among the general population. Our results identify several novel associations related to specific immune processes that may contribute to risk of myocardial fibrosis and subsequent HF among both PWH and PWOH.

Humans↗

PubMed2007

Estimating the benefit of an HIV-1 vaccine that reduces viral load set point.

Vaccines designed to induce cell-mediated immune responses against human immunodeficiency virus (HIV)-1 are being developed. Such vaccines are unlikely to provide sterilizing immunity but may be associated with reduced viral set points after infection. We modeled the potential impact of a vaccine that reduces viral set point after infection, using natural history data from 311 HIV-1 seroconverters. Log-normal parametric regression models were used to estimate the log median time to events of interest. Relative times were estimated for those with viral load set points of 30,000 copies/mL (reference group) versus those with lower viral set points. The time to key clinical events in the course of HIV-1 disease progression was significantly extended for those with viral set points 0.5-1.25 log(10) copies/mL lower than the reference group. By quantifying the anticipated clinical benefits associated with a reduction in viral set point, these findings support the use of virologic end points in HIV-1 vaccine trials.

AIDS Vaccines↗

PubMed2007

Assessing immunophenotyping performance: proficiency-validation for adopting improved flow cytometry methods.

BACKGROUND: The continuous improvement and evolution of immune cell phenotyping requires periodic upgrading of laboratory methods and technology. Flow cytometry laboratories that are participating in research protocols sponsored by the NIAID are required to perform "switch" studies to validate performance before methods for T-cell subset analysis can be changed. METHODS: Switch studies were conducted among the four flow cytometry laboratories of the Multicenter AIDS Cohort Study (MACS), comparing a 2-color, lyse-wash method and a newer, 3-color, lyse no-wash method. Two of the laboratories twice failed to satisfy the criteria for acceptable differences from the previous method. Rather than repeating more switch studies, these laboratories were allowed to adopt the 3-color, lyse no-wash method. To evaluate the impact of the switch to the new method at these two sites, their results with the new method were evaluated within the context of all laboratories participating in the NIH-NIAID-Division of AIDS Immunology Quality Assurance (IQA) proficiency-testing program. RESULTS: Laboratory performance at these two sites substantially improved relative to the IQA standard test results. Variation across the four MACS sites and across replicate samples was also reduced. CONCLUSIONS: Although switch studies are the conventional method for assessing comparability of laboratory methods, two alternatives to the requirement of repeating failed switch studies should be considered: (1) test the new method and assess performance on the proficiency testing reference panel, and (2) prior to adoption of the new methods, use both the old and the new method on the reference panel samples and demonstrate that performance with the new method is better according to standard statistical procedures. These alternatives may help some laboratories' transition to a new and superior methodology more quickly than if they are required to attempt multiple, serial switch studies.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Novel pathway for induction of latent virus from resting CD4(+) T cells in the simian immunodeficiency virus/macaque model of human immunodeficiency virus type 1 latency.

Although combination therapy allows the suppression of human immunodeficiency virus type 1 (HIV-1) viremia to undetectable levels, eradication has not been achieved because the virus persists in cellular reservoirs, particularly the latent reservoir in resting CD4(+) T lymphocytes. We previously established a simian immunodeficiency virus (SIV)/macaque model to study latency. We describe here a novel mechanism for the induction of SIV from latently infected resting CD4(+) T cells. Several human cell lines including CEMx174 and Epstein-Barr virus-transformed human B-lymphoblastoid cell lines mediated contact-dependent activation of resting macaque T cells and induction of latent SIV. Antibody-blocking assays showed that interactions between the costimulatory molecule CD2 and its ligand CD58 were involved, whereas soluble factors and interactions between T-cell receptors and major histocompatibility complex class II were not. Combinations of specific antibodies to CD2 also induced T-cell activation and virus induction in human resting CD4(+) T cells carrying latent HIV-1. This is the first demonstration that costimulatory signals can induce latent virus without the coengagement of the T-cell receptor, and this study might provide insights into potential pathways to target latent HIV-1.

Animals↗

PubMed2006

Impact of inversion of the CD4/CD8 ratio on the natural history of HIV-1 infection.

BACKGROUND: HIV-1 infection is characterized by an inverted CD4/CD8 T-cell ratio, but the distribution of inversions over time after seroconversion and whether delay of inversion is associated with a favorable prognosis are not known. METHODS: T-cell counts and clinical outcomes among men in the Multicenter AIDS Cohort Study who had incident HIV-1 infection before December 31, 1995 were analyzed by Kaplan-Meier and Cox proportional hazards methods. Results were also analyzed by time-dependent multivariate methods to adjust for CD4 lymphocyte counts, viral loads, age, race, and polymorphisms in host chemokine receptor genes (CCR5-Delta32 and CCR2-64I). RESULTS: Among 424 cases whose date of seroconversion was known to within +/-4.5 months, 317, 52, and 55 inverted their CD4/CD8 ratio within less than 1, 1 to 2, and more than 2 years of seroconversion, respectively. Longer time to inversion was significantly associated with longer time to AIDS, even after adjusting for CD4 lymphocyte count and viral load at the first seropositive visit and over the first 3 seropositive visits. Of the 6 seroconverters who had more than 500 CD4 lymphocytes 10 years after seroconversion without receiving highly active antiretroviral therapy, 5 took more than 2 years to invert their CD4/CD8 ratio. CONCLUSIONS: Time from HIV-1 seroconversion to inversion of the CD4/CD8 ratio independently predicted time to AIDS. Early measurements of the CD4/CD8 ratio until inversion occurs may identify people likely to become long-term nonprogressors or slow progressors, thus facilitating detailed studies of the mechanism of HIV-1 disease progression.

Adult↗

PubMed2006

Cohort- and time-specific associations of CTLA4 genotypes with HIV-1 disease progression.

BACKGROUND: CTLA4 in the chromosome 2q33 region encodes cytotoxic T-lymphocyte (CTL) associated antigen 4, which downregulates CTL responses. We examined the relationships between common CTLA4 variants and several outcomes of HIV-1 infection in adults and adolescents. METHODS: We studied 765 HIV-1-infected persons: 558 Caucasian seroconverters from three cohorts (MACS, ACS, and DCG) and 207 infected adolescents (mostly female) from another cohort (REACH) of mixed ethnicity. Single nucleotide polymorphisms in CTLA4 promoter (-1147C/T, -658C/T, -318C/T), coding sequence (49A/G) and the 3' untranslated region (CT60A/G) were resolved by PCR-based techniques. Repeated measures and survival analyses were used to test allelic and haplotypic associations with HIV-1 viral load (VL) and time to AIDS, respectively. RESULTS: Individuals carrying -318T or the (-1147) T-(-318) T haplotype had elevated HIV-1 VL in MACS and REACH but reduced VL in DCG and ACS participants. Time-dependent associations of CTLA4-318T with VL were observed in MACS and REACH (P = 0.03-0.09). In Cox regression models adjusted for age and established contributory markers in CCR5 and HLA class I genes, CTLA4-318T was associated with rapid progression to AIDS in MACS (relative hazard 1.69; 95% confidence interval, 1.15-2.49; P < 0.01) as opposed to a non-significant slower disease progression in ACS and no appreciable association in DCG. CONCLUSIONS: Association of CTLA4 genotypes with clinical and virological outcomes following HIV-1 infection appeared to vary with time and among the cohorts. Further analyses in conjunction with other biologically and positionally related genes, such as CD28 and ICOS, may help explain the disparate findings.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Evaluation of a low-cost method, the Guava EasyCD4 assay, to enumerate CD4-positive lymphocyte counts in HIV-infected patients in the United States and Uganda.

OBJECTIVE: To evaluate the EasyCD4 assay, a less expensive method to enumerate CD4+ lymphocytes, in resource-limited settings. DESIGN: Cross-sectional study conducted in the United States and Uganda. METHODS: We compared CD4+ cell counts obtained on replicate samples from HIV-infected patients by the EasyCD4 assay, a microcapillary flow-based system, and by standard flow cytometry or FACSCount with linear regression and the Bland-Altman method. RESULTS: Two hundred eighteen samples were analyzed (77 in the United States and 141 in Uganda). In the United States, mean +/- SD CD4 was 697 +/- 438 cells/microL by standard flow cytometry and 688 +/- 451 cells/microL by EasyCD4. In Uganda, the mean +/- SD CD4 was 335 +/- 331 cells/microL by FACSCount and 340 +/- 327 cells/microL by EasyCD4. The 2 methods were highly correlated (US cohort, r2 = 0.97, slope = 1.0, intercept = -18; Ugandan cohort, r2 = 0.92; slope = 0.95; intercept = 23). The mean differences in CD4 cell counts were 9.0 and -4.6 cells/microL for the US and Ugandan cohorts, respectively, and they were not significant in either cohort. In the Ugandan cohort, sensitivity and specificity of the EasyCD4 for CD4 below 200 cells/microL were 90% and 98%, respectively. Positive predictive value was 96%; negative predictive value was 93%. CONCLUSIONS: Our results suggest that EasyCD4 may be used with high positive and negative predictive value in resource-limited settings.

CD4 Lymphocyte Count↗

PubMed2006

Longitudinal assessment of de novo T cell production in relation to HIV-associated T cell homeostasis failure.

Loss of circulating CD4+ T cells in HIV-1 disease is balanced by CD8+ lymphocytosis to maintain normal CD3+ T cell counts [blind T cell homeostasis (TCH)]. However, for unknown reasons TCH generally fails 1.5-2.5 years before clinically defined AIDS. We investigated whether TCH failure was associated with changes in thymic production of T cells. Using specimens stored prospectively in the Multicenter AIDS Cohort Study (MACS), we measured expression of signal-joint T cell receptor excision circles (sjTRECs), a marker for thymic T cell production, and the fraction of proliferating naive and memory T cells during a 6-8 year period bracketing TCH failure. Segmented regression modeling assessed (1) rates of change in TREC levels before and after TCH failure, and (2) whether these were affected by cellular proliferation, which may dilute sjTREC levels. TCH failure was associated with a large decline in sjTREC (median 1109-fold, p = 0.028); the rate of this decline was only slightly affected when increased proliferation of naive T cells or other peripheral lymphocytes was taken into account. Preferential loss of naive CD4+ T cells was also noted before TCH failure, as has been seen in other studies. These results suggest that deficits in de novo T cell production, either through the decline of thymic function or the destruction of naive T cells, are likely to play an important role in TCH failure and progression of HIV-1 disease.

CD3 Complex↗

PubMed2006

High frequency of highly active antiretroviral therapy modifications in patients with acute or early human immunodeficiency virus infection.

STUDY OBJECTIVES: To examine the frequency of highly active antiretroviral therapy (HAART) modifications, the reasons for these modifications, and toxicities of these drugs in patients receiving their first HAART regimen after a diagnosis of acute (< 2 mo from infection) or early (2-12 mo) human immunodeficiency virus (HIV) infection. PATIENTS: Fifty-one patients who were enrolled in the Acute Infection and Early Disease Research Program at a Baltimore, Maryland, site between January 1, 1998, and April 30, 2002, and who chose to start HAART. MEASUREMENTS AND MAIN RESULTS: Time from initiation of therapy to first modification-defined as change in any HAART drug without an interruption in therapy or as simultaneous discontinuation of all drugs within the regimen-and time from initiation of therapy to reinitiation of therapy were recorded, as well as reasons for modification and reinitiation. With a median follow-up of 1,549 days, 21 (41%) of 51 patients received HAART continuously, but only 10 (20%) continued to receive their original regimen without any modification. Among the 41 patients (80%) who received modified therapy, the main reasons for the first modification were toxicity (16 patients), nonadherence (8), and new data on treatment efficacy or safety (8). Of 30 patients who stopped HAART, 18 restarted HAART at a later time. CONCLUSION: The high frequency of treatment modification among patients treated after acute or early HIV infection underscores the importance of determining the usefulness of antiretroviral therapy early in HIV infection, and the need for more tolerable regimens if HAART is to be started at this stage.

Acute Disease↗

PubMed2005

Effect of highly active antiretroviral therapy on multiple AIDS-defining illnesses among male HIV seroconverters.

The effect of highly active antiretroviral therapy (HAART) on multiple acquired immunodeficiency syndrome (AIDS)-defining illnesses remains unclear. Between 1984 and 2005, 573 male human immunodeficiency virus seroconverters in four US urban centers were followed for a median of 9.7 years. During follow-up, 345, 113, 50, and 65 men incurred 0, 1, 2, and >2 AIDS-defining illnesses, respectively. The authors extend the Cox proportional hazards model to determine whether the effect of HAART, as measured by calendar periods, persists beyond the first AIDS-defining illness. After adjustment for race and age at seroconversion, the hazards of a first through third AIDS-defining illness in the HAART calendar period (beyond July 1995) were 0.31 (95% confidence interval (CI): 0.21, 0.46), 0.39 (95% CI: 0.22, 0.74), and 0.33 (95% CI: 0.14, 0.79), respectively, relative to the monotherapy and combination therapy reference calendar period (January 1990-July 1995) and therefore did not attenuate with the number of prior AIDS-defining illnesses (p for homogeneity = 0.83). After the authors averaged over multiple AIDS-defining illnesses, the hazard of an AIDS-defining illness in the HAART calendar period was 0.34 (95% CI: 0.25, 0.45) relative to the reference calendar period. HAART protects against initial and subsequent AIDS-defining illnesses, whose inclusion in analysis markedly increased the precision of the estimated hazard ratio.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study.

OBJECTIVE: To estimate insulin resistance and its relationship to antiretroviral therapy (ART) in a cohort of HIV-infected persons with comparison to HIV-seronegative controls. DESIGN: Prospective cohort of 533 HIV-infected and 755 HIV-seronegative men in the Multicenter AIDS Cohort Study evaluated at 6-month intervals between 1999 and 2003. METHODS: Recent ART exposure was assessed by type of treatment in the preceding 6 months [i.e., no ART, monotherapy, combination ART, or highly active antiretroviral therapy (HAART) with and without a protease inhibitor (PI)]. Cumulative exposure was determined for the three major ART classes and for individual medications within each class. Two endpoints, a modified QUICKI index, 100 x 1/[log10(glucose) + log10(insulin)] and fasting hyperinsulinemia (insulin > 15 microU/ml), were assessed. All statistical models were adjusted for age, body mass index, race, nadir CD4 cell count, hepatitis C serostatus and family history of diabetes mellitus. RESULTS: Each of the HIV-infected groups had higher odds of hyperinsulinemia and lower mean QUICKI than the HIV-seronegative men. Each additional year of exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI) was associated with increased odds of hyperinsulinemia [odds ratio (OR), 1.08; 95% confidence interval (CI), 1.02-1.13) and a lower QUICKI (-0.04; 95% CI, -0.07 to -0.01). Cumulative exposure to non-nucleoside analogue reverse transcriptase inhibitors or PI drugs was not associated with either insulin resistance marker. Of individual medications examined, stavudine was associated with the highest risk of hyperinsulinemia (OR, 1.2; 95% CI, 1.2-1.3). CONCLUSIONS: Fasting surrogate markers suggest increased insulin resistance in HIV-infected men, which is related to cumulative NRTI exposure.

Adult↗

PubMed2005

Individual variation in CD4 cell count trajectory among human immunodeficiency virus-infected men and women on long-term highly active antiretroviral therapy: an application using a Bayesian random change-point model.

The authors evaluated population- and individual-level CD4-positive T-lymphocyte (CD4 cell) count trajectories over a 7-year period (July 1995-March 2004) following initiation of highly active antiretroviral therapy (HAART) in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. The study population included 404 human immunodeficiency virus (HIV)-infected men and 609 HIV-infected women who 1) had a CD4 cell count measurement available from their last pre-HAART study visit, 2) provided at least four post-HAART CD4 cell count measurements, and 3) reported HAART usage for at least 80% of the post-HAART visits. The CD4 cell count trajectory was analyzed by means of a Bayesian random change-point model. The results indicated that CD4 cell count trajectories for long-term frequent HAART users can be well modeled with change points at both the population and individual levels. At the population level, regardless of CD4 cell count before HAART initiation, the gains in CD4 cell count ended approximately 2 years after HAART initiation in both men and women. At the individual level, 35% of men in the Multicenter AIDS Cohort Study versus 25% of women in the Women's Interagency HIV Study had a statistically significant change in CD4 cell count trajectory within 7 years after HAART initiation.

Adult↗

PubMed2005

Use of total lymphocyte count and hemoglobin concentration for monitoring progression of HIV infection.

BACKGROUND: Prognostic markers for HIV monitoring are needed for resource-limited regions. Prior research has demonstrated rapid declines in total lymphocyte count (TLC) and hemoglobin levels before AIDS, but the prognostic accuracy of these declines has not been examined prospectively. METHODS: Longitudinal TLC and hemoglobin data from men in the Multicenter AIDS Cohort Study (MACS) before the introduction of potent HIV therapy were used to identify the first time when the TLC was 33% per year, and hemoglobin declined by >11.6% per year. The prognostic value of these declines for AIDS was evaluated by Cox regression models and Kaplan-Meier survival curves. RESULTS: Rapid declines in TLC or hemoglobin were associated with progression to AIDS (relative hazard [RH]=4.70, 95% confidence interval [CI]: 3.23-6.86 for TLC; RH=5.55, 95% CI: 3.69-8.36 for hemoglobin). The World Health Organization criterion for initiating therapy, a TLC 1200 cells/mm, a rapid decline in TLC or hemoglobin was strongly associated with progression to AIDS (RH=2.53, 95% CI: 1.56-4.10 for TLC; RH=5.28, 95% CI: 3.11-8.97 for hemoglobin). CONCLUSIONS: In the MACS, rapid declines in TLC or hemoglobin concentration indicated an increased likelihood of progression of HIV infection to AIDS. These results support the potential utility of these markers for monitoring HIV-infected people in resource-limited regions, but critical levels and rates of decline of markers for such regions remain to be defined.

Biomarkers↗

PubMed2005

Marginal structural models for estimating the effect of highly active antiretroviral therapy initiation on CD4 cell count.

The effect of highly active antiretroviral therapy (HAART) on the evolution of CD4-positive T-lymphocyte (CD4 cell) count among human immunodeficiency virus (HIV)-positive participants was estimated using inverse probability-of-treatment-and-censoring (IPTC)-weighted estimation of a marginal structural model. Of 1,763 eligible participants from two US cohort studies followed between 1996 and 2002, 60 percent initiated HAART. The IPTC-weighted estimate of the difference in mean CD4 cell count at 1 year among participants continuously treated versus those never treated was 71 cells/mm3 (95% confidence interval: 47.5, 94.6), which agrees with the reported results of randomized experiments. The corresponding estimate from a standard generalized estimating equations regression model that included baseline and most recent CD4 cell count and HIV type 1 RNA viral load as regressors was 26 cells/mm3 (95% confidence interval: 17.7, 34.3). These results indicate that nonrandomized studies of HIV treatment need to be analyzed with methods (e.g., IPTC-weighted estimation) that, in contrast to standard methods, appropriately adjust for time-varying covariates that are simultaneously confounders and intermediate variables. The 1-year estimate of 71 cells/mm3 was followed by an estimated continued increase of 29 cells/mm3 per year (estimated effect at 6 years: 216 cells/mm3), providing evidence that the large short-term effect found in randomized experiments persists and continues to improve over 6 years.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Association between highly active antiretroviral therapy and hypertension in a large cohort of men followed from 1984 to 2003.

OBJECTIVE: UO1-AI-35041: To examine the impact of HIV infection and highly active antiretroviral therapy on systolic and diastolic hypertension. DESIGN: Cohort study with semi-annual assessment of the outcome. METHODS: We studied 5578 participants of the Multicenter AIDS Cohort Study with blood pressure measurements obtained between 1984 and 2003. The primary outcomes were systolic hypertension (SH; systolic blood pressure > 140 mmHg) and diastolic hypertension (DH; diastolic blood pressure > 90 mmHg). Statistical analyses were performed using multiple logistic regression with robust variance estimation. RESULTS: Of the 84 813 person-visits available for analysis, 7.3 and 8.0% showed SH and DH, respectively. Controlling for age, race, body mass index, and smoking, HIV positive men not taking antiretroviral therapy were significantly less likely than HIV negative men to have SH [odds ratio (OR), 0.79; 95% confidence interval (CI), 0.70-0.89], as were men taking mono/combination therapy (OR, 0.69; 95% CI, 0.59-0.80). The prevalence of SH among men taking highly active antiretroviral therapy (HAART) for less than 2 years was similar to that among HIV negative men (OR, 1.06; 95% CI, 0.87-1.30), but was significantly higher thereafter; for 2 to 5 years of HAART (OR, 1.51; 95% CI, 1.25-1.82) and for more than 5 years of HAART (OR, 1.70; 95% CI, 1.34-2.16). In contrast, DH was not significantly higher among men with prolonged HAART use compared to that among HIV negative controls. CONCLUSIONS: Prolonged HAART use was significantly associated with a higher prevalence of SH. This finding suggests that individuals taking HAART may be at increased risk of developing hypertension-related conditions and underscores the importance of blood pressure monitoring among these individuals.

Adult↗

PubMed2005

Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study.

BACKGROUND: The risk of diabetes mellitus (DM) in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) has not been well defined. METHODS: We conducted an analysis in the Multicenter AIDS Cohort Study to determine the prevalence and incidence of DM in this cohort of HIV-infected and HIV-seronegative men. Prevalence analysis included 1278 men (710 HIV seronegative and 568 HIV infected, 411 receiving HAART) with fasting glucose concentration determinations at baseline. Incidence analysis included 680 of these 1278 men who at the baseline visit had a fasting glucose concentration of 98 mg/dL (5.4 mmol/L) or less, no self-reported history of DM, and no self-reported use of antidiabetic medication. Diabetes mellitus was defined as a fasting glucose concentration of 126 mg/dL (7 mmol/L) or higher, self-reported diagnosis of DM, or self-reported use of antidiabetic medication. RESULTS: Fifty-seven (14%) of the 411 HIV-infected men using HAART at the baseline visit had prevalent DM compared with 33 (5%) of the 711 HIV-seronegative men (prevalence ratio = 4.6; 95% confidence interval, 3.0-7.1, adjusted for age and body mass index [calculated as weight in kilograms divided by the square of height in meters]). The rate of incident DM was 4.7 cases per 100 person-years among HIV-infected men using HAART compared with 1.4 cases per 100 person-years among HIV-seronegative men (rate ratio = 4.11; 95% confidence interval, 1.85-9.16, adjusted for age and body mass index), during the 4-year observation period, based on a median follow-up of 2.3 years. CONCLUSION: The incidence of DM in HIV-infected men with HAART exposure was greater than 4 times that of HIV-seronegative men, representing a risk that is higher than previous estimates.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Interruption and discontinuation of highly active antiretroviral therapy in the multicenter AIDS cohort study.

OBJECTIVE: Identify the determinants and consequences of interrupting and discontinuing highly active antiretroviral therapy (HAART) among a population-based cohort of HIV-infected men. METHODS: Longitudinal analyses were applied to 2916 person-visit pairs (589 men) of continuous HAART use, 243 person-visit pairs (154 men) during which HAART was interrupted, and 151 person-visit pairs (130 men) in which HAART was discontinued by the second visit. HIV RNA increase was defined as > or =1 log10 copies/mL across the visit pairs. RESULT: : Younger age, black race, geographic location, higher HIV RNA level, depression, shorter time on HAART, lower medication adherence, and not taking a lamivudine-containing regimen predicted interrupting HAART use. Younger age, higher HIV RNA level, depression, and taking an abacavir- or lopinavir-containing regimen predicted discontinuing HAART. Among men with < or =1000 HIV RNA copies/mL, approximately 5% of those who interrupted HAART for < or =7 days and those who continued HAART had an HIV RNA increase. Men with longer interruptions and HAART discontinuers had significantly higher rates of HIV RNA increases (35.7% and 70.5%, respectively). Discontinuation and long interruptions resulted in lower CD4 cell counts. CONCLUSIONS: Host characteristics play a role in short interruptions, whereas longer interruptions may be clinically indicated. These longer stoppages had further virologic and immunologic consequences, however.

Adult↗

PubMed2005

Application of case-crossover and case-time-control study designs in analyses of time-varying predictors of T-cell homeostasis failure.

PURPOSE: To evaluate the association of sexual behavior and recreational drug exposures with T-cell homeostasis failure (TCHF), which corresponds to the onset of a rapid decline in an individual's T lymphocyte count, which occurs on average approximately 1.75 years prior to an initial diagnosis of acquired immunodeficiency syndrome (AIDS). METHODS: A case-crossover design and a case-time-control design, both nested within the Multicenter AIDS Cohort Study of 4954 homosexual and bisexual men initiated in 1983. RESULTS: In the case-crossover analysis, use of both recreational drugs and hashish were found to be protective against TCHF (odds ratios < or = 0.41), based on comparisons with four earlier control periods. However, a significant decreasing trend in the prevalence of these exposures was observed over time, thus motivating the implementation of the case-time-control design. Using the latter approach, the associations of drug use (odds ratio=0.53; 95% confidence interval (CI): 0.22, 1.28) and hashish use (odds ratio=0.46; 95% CI: 0.20, 1.05) with TCHF were no longer statistically significant. CONCLUSIONS: The difference in inferences between these approaches demonstrates the importance of evaluating temporal trends in exposures when using a case-crossover design.

Acquired Immunodeficiency Syndrome↗