Andrew H. Kaplan

A Prospective Study of Predictors of Adherence to Combination Antiretroviral Medication

AbstractOBJECTIVE: Adherence to complex antiretroviral therapy (ART) is critical for HIV treatment but difficult to achieve. The development of interventions to improve adherence requires detailed information regarding barriers to adherence. However, short follow-up and inadequate adherence measures have hampered such determinations. We sought to assess predictors of long-term (up to 1 year) adherence to newly initiated combination ART using an accurate, objective adherence measure. DESIGN: A prospective cohort study of 140 HIV-infected patients at a county hospital HIV clinic during the year following initiation of a new highly active ART regimen. MEASURES AND MAIN RESULTS: We measured adherence every 4 weeks, computing a composite score from electronic medication bottle caps, pill count and self-report. We evaluated patient demographic, biomedical, and psychosocial characteristics, features of the regimen, and relationship with one’s HIV provider as predictors of adherence over 48 weeks. On average, subjects took 71% of prescribed doses with over 95% of patients achieving suboptimal (<95%) adherence. In multivariate analyses, African-American ethnicity, lower income and education, alcohol use, higher dose frequency, and fewer adherence aids (e.g., pillboxes, timers) were independently associated with worse adherence. After adjusting for demographic and clinical factors, those actively using drugs took 59% of doses versus 72% for nonusers, and those drinking alcohol took 66% of doses versus 74% for nondrinkers. Patients with more antiretroviral doses per day adhered less well. Participants using no adherence aids took 68% of doses versus 76% for those in the upper quartile of number of adherence aids used. CONCLUSIONS: Nearly all patients’ adherence levels were suboptimal, demonstrating the critical need for programs to assist patients with medication taking. Interventions that assess and treat substance abuse and incorporate adherence aids may be particularly helpful and warrant further study.

CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency.

The CD8+ T-cell response is central to control and eventual elimination of persistent viral infections. Although it might be expected that CD8+ T-cell activation would be associated with a better clinical outcome during viral infections, in long-term HIV-1 infection, high levels of CD8+ T-cell activation are instead associated with faster disease progression. In this study, cell surface expression of CD38, a flow cytometric marker of T-cell activation of CD8+ T cells, had predictive value for HIV-1 disease progression that was in part independent of the predictive value of plasma viral burden and CD4+ T-cell number. Measurements of CD38 antigen expression on CD8+ T cells in HIV-1-infected patients may be of value for assessing prognosis and the impact of therapeutic interventions. The pathogenetic reason why CD8+ T-cell activation is associated with poor outcome in HIV-1 disease remains unknown. Possibly CD8+ T-cell activation contributes to immunologic exhaustion, hyporesponsiveness of T cells to their cognate antigens, or perturbations in the T-cell receptor repertoire.

How Well Do Clinicians Estimate Patients' Adherence to Combination Antiretroviral Therapy?

AbstractOBJECTIVE: Adherence to combination antiretroviral therapy is critical for clinical and virologic success in HIV-infected patients. To combat poor adherence, clinicians must identify nonadherent patients so they can implement interventions. However, little is known about the accuracy of these assessments. We sought to describe the accuracy of clinicians’ estimates of patients’ adherence to combination antiretroviral therapy. SETTING: Public HIV clinic. DESIGN: Prospective cohort study. During visits, we asked clinicians (nurse practitioners, residents and fellow, and their supervising attending physicians) to estimate the percentage of antiretroviral medication taken by patients over the last 4 weeks and predicted adherence over the next 4 weeks. Adherence was measured using electronic monitoring devices, pill counts, and self-reports, which were combined into a composite adherence measure. PATIENTS AND PARTICIPANTS: Clinicians estimated 464 episodes of adherence in 82 patients. RESULTS: Among the 464 adherence estimates, 264 (57%) were made by principal care providers (31% by nurse practitioners, 15% by fellows, 6% by residents, and 5% by staff physicians) and 200 (43%) by supervising attending physicians. Clinicians’ overestimated measured adherence by 8.9% on average (86.2% vs 77.3%). Greater clinician inaccuracy in adherence prediction was independently associated with higher CD4 count nadir (1.8% greater inaccuracy for every 100 CD4 cells, P=.005), younger patient age (3.7% greater inaccuracy for each decade of age, P=.02), and visit number (P=.02). Sensitivity of detecting nonadherent patients was poor (24% to 62%, depending on nonadherence cutoff). The positive predictive value of identifying a patient as nonadherent was 76% to 83%. CONCLUSIONS: Clinicians tend to overestimate medication adherence, inadequately detect poor adherence, and may therefore miss important opportunities to intervene to improve antiretroviral adherence.

Repeated Measures Longitudinal Analyses of HIV Virologic Response as a Function of Percent Adherence, Dose Timing, Genotypic Sensitivity, and Other Factors

Background: Adherence to antiretroviral medications is critical to achieving HIV viral suppression. Studies have been limited to cross-sectional analyses using measures that reflect only the percentage of prescribed doses taken (percent adherence), however. The contribution of dose timing and other factors to achieving virologic suppression has received less scrutiny. Methods: In a longitudinal study, we collected detailed adherence information using multiple tools along with demographic, clinical, social-behavioral, and virologic measures. Subjects were followed for 48 weeks. Percent adherence, dose-timing, genotypic sensitivity, and virologic outcomes were collected every 4 weeks. Repeated measures mixed effects models (RMMEMs) were used to model the relation between virologic outcomes and adherence as well as genotypic sensitivity and others. Results: Of the 141 subjects, mean percent adherence was 73% with a downward trend. Viral load (VL) dropped significantly (P = 0.01) over time. RMMEMs revealed that higher genotypic sensitivity, higher percent adherence, lower baseline VL, longer inclusion in the study, earlier HIV stage, and smaller dose-timing error were significantly associated with lower VL. In multivariate modeling, a 0.50 increase in the genotypic sensitivity score, a 10% increase in adherence, and a decrease of 3 hours of dose-timing error were associated with a decrease in log10 HIV RNA at 48 weeks of 0.69, 0.54, and 0.48, respectively (P < 0.05 for each). Conclusions: Long-term viral suppression requires consistent and high percent adherence accompanied by optimal interdose intervals. Efforts to improve viral outcomes should address not only missed doses but excessive variation in dose timing and prevention of adherence decline over time. Preventing the development and transmission of resistant variants is also critically important.

The unexpected movement of the HIV epidemic in the Southeastern United States: transmission among college students.

Background:Approximately 16 million people are enrolled in institutions of higher learning in the United States. However, college students have not been perceived as at high risk for HIV infection. In early 2003, acute HIV infection was diagnosed in 2 men attending college in North Carolina. We describe an epidemiologic investigation of newly diagnosed HIV infection in men attending college in North Carolina. Methods:We reviewed state surveillance records examining new HIV diagnoses in men 18-30 years old between January 1, 2000 and December 31, 2003, living in 69 North Carolina counties. Risk behavior and demographic information for HIV-infected men enrolled in college were compared with HIV-infected male nonenrollees. Results:Of the 735 records available for review, 84 (11%) were college men. Eighty-seven percent of college men were African American and 92% were men who have sex with men (MSM) or men who have sex with men and women (MSM/W). Compared with noncollege men, college men were more likely to be African American (odds ratio 3.70, 95% CI = 1.86-7.54), to report meeting sex partners at bars or dance clubs (odds ratio 3.01, 95% CI = 1.77-5.10) or on the Internet/chat lines (odds ratio 4.95, 95% CI = 2.53-9.64), or to report use of “ecstasy” or club drugs (odds ratio 4.51, 95% CI = 1.15-15.40). Newly diagnosed HIV infection was found in men in 37 colleges located in North Carolina or surrounding states and a sexual partner network investigation linked 21 colleges, 61 students, and 8 partners of students. Conclusion:We describe an epidemic of HIV infection occurring in North Carolina college students, primarily involving African American MSM and MSM/W. College students represent an at-risk, accessible population, which deserves further HIV prevention interventions.

Men who have sex with men and women: A unique risk group for HIV transmission on North Carolina college campuses

Objective: To better understand the role that men who have sex with men and women (MSM/W) play in the spread of HIV in young adults in North Carolina, we determined the prevalence of MSM/W among newly diagnosed HIV-infected men, compared social and behavioral characteristics of this group with MSM and MSW, and examined the sexual networks associated with HIV-infected college students among these groups. Methods: We reviewed state HIV surveillance records for all new diagnoses of HIV in males 18 to 30 years living in North Carolina between January 1, 2000, and December 31, 2004. Results: Of 1105 records available for review, 15% were MSM/W and 13% were college students. Compared with MSM, MSM/W were more likely to be enrolled in college, to report >10 sex partners in the year before diagnosis, or have sex partners who were also MSM/W. Sexual network analysis of the HIV-infected college students revealed that MSM/W occupied a central position. Of 20 individuals who described themselves as either MSW or abstinent at the time of their initial voluntary counseling and testing visit, 80% reported that they were either MSM or MSM/W during follow up. Discussion: MSM/W represent a unique risk group within the population of MSM that deserve further investigation. College MSM/W appear to occupy a unique, central place in the network of HIV-infected students.

Initial Cleavage of the Human Immunodeficiency Virus Type 1 GagPol Precursor by Its Activated Protease Occurs by an Intramolecular Mechanism

ABSTRACT Processing of the GagPol polyprotein precursor of human immunodeficiency virus type 1 (HIV-1) is a critical step in viral assembly and replication. The HIV-1 protease (PR) is translated as part of GagPol and is both necessary and sufficient for precursor processing. The PR is active only as a dimer; enzyme activation is initiated when the PR domains in two GagPol precursors dimerize. The precise mechanism by which the PR becomes activated and the subsequent initial steps in precursor processing are not well understood. However, it is clear that processing is initiated by the PR domain that is embedded within the precursor itself. We have examined the earliest events in precursor processing using an in vitro assay in which full-length GagPol is cleaved by its embedded PR. We demonstrate that the embedded, immature PR is as much as 10,000-fold less sensitive to inhibition by an active-site PR inhibitor than is the mature, free enzyme. Further, we find that different concentrations of the active-site inhibitor are required to inhibit the processing of different cleavage sites within GagPol. Finally, our results indicate that the first cleavages carried out by the activated PR within GagPol are intramolecular. Overall, our data support a model of virus assembly in which the first cleavages occur in GagPol upstream of the PR. These intramolecular cleavages produce an extended form of PR that completes the final processing steps accompanying the final stages of particle assembly by an intermolecular mechanism.

Effects of influenza vaccination in HIV-infected adults: a double-blind, placebo-controlled trial.

Annual influenza vaccine is recommended for persons with HIV infection. Recent reports indicate that immunizations may increase HIV replication in infected individuals. Forty-seven HIV-infected patients were randomized to influenza vaccine or saline placebo using a double blind study design. One month after vaccination, plasma HIV-1 RNA increased in the vaccinated but not placebo group (p = 0.029). At 3 months, CD4% dropped an average of 1.6 points in the vaccinated group compared to an increase of 0.1 points in the placebo group (p = 0.039). Patients on stable antiretroviral regimens had CD4% drop an average of 2.3 points in the vaccinated group at 3 months versus 0.1 points in the placebo group (p = 0.015). It is concluded that HIV-infected patients are at risk for increased HIV replication and decreases in CD4% following influenza vaccination. Since influenza has not been associated with significant morbidity in this population, further study of routine influenza vaccination for HIV-infected patients is warranted.

Processing sites in the human immunodeficiency virus type 1 (HIV-1) Gag-Pro-Pol precursor are cleaved by the viral protease at different rates

We have examined the kinetics of processing of the HIV-1 Gag-Pro-Pol precursor in an in vitro assay with mature protease added in trans. The processing sites were cleaved at different rates to produce distinct intermediates. The initial cleavage occurred at the p2/NC site. Intermediate cleavages occurred at similar rates at the MA/CA and RT/IN sites, and to a lesser extent at sites upstream of RT. Late cleavages occurred at the sites flanking the protease (PR) domain, suggesting sequestering of these sites. We observed paired intermediates indicative of half- cleavage of RT/RH site, suggesting that the RT domain in Gag-Pro-Pol was in a dimeric form under these assay conditions. These results clarify our understanding of the processing kinetics of the Gag-Pro-Pol precursor and suggest regulated cleavage. Our results further suggest that early dimerization of the PR and RT domains may serve as a regulatory element to influence the kinetics of processing within the Pol domain.

Transient renewal of thymopoiesis in HIV-infected human thymic implants following antiviral therapy

Stem cell gene therapy strategies for AIDS require that differentiation-inducing stromal elements of HIV-infected individuals remain functionally intact to support the maturation of exogenous progenitor cells into mature CD4+ cells. To investigate the feasibility of stem cell reconstitution strategies in AIDS, we used the SCID-hu mouse to examine the ability of HIV-infected CD4+ cell-depleted human thymic implants to support renewed thymopoiesis. Here we report that following treatment of these implants with antiretroviral drugs, new thymopoiesis is initiated. This suggests that antiviral therapies might allow de novo production of T lymphocytes and provides support for the concept of therapeutic strategies aimed at reconstitution of the peripheral CD4+ T-cell compartment.