Biomedical subjects

Andrew H Kaplan

Publications and source records attributed to Andrew H Kaplan.

At least 19 recordsLinked to original sources

PubMed2007

Repeated measures analyses of dose timing of antiretroviral medication and its relationship to HIV virologic outcomes.

Medication adherence is a critical predictor of the effectiveness of antiretroviral medications in the treatment of HIV/AIDS. Studies of adherence, however, have focused primarily on the per cent of prescribed doses taken (per cent adherence). In the Adherence and Efficacy of Protease Inhibitor Therapy study, we collected detailed adherence data including dose timing information as well as data regarding patients' virologic responses. For 48 weeks, adherence data and virologic outcomes were collected every 4 weeks, and demographics and other measures were collected at baseline and at weeks 8, 24, and 48. We constructed eight different dose timing error (DTE) measures and evaluated their associations with virologic outcomes using longitudinal analyses. Repeated measures mixed effect models were fitted to evaluate the predicting power of each of the DTE measures. Among 52 036 electronically measured doses obtained from 122 patients, DTE measures significantly predicted virologic outcomes. Of the eight different DTE measures, the six DTE measures were significantly predictive of virologic outcomes even after controlling for per cent adherence. In conclusion, we identified several measures of DTE that explain HIV virologic outcomes not captured by traditional adherence measures. Investigations of adherence to antiretrovirals would benefit from measuring not only per cent adherence but dose timing adherence.

Adult↗

PubMed2006

A practical method to calibrate self-reported adherence to antiretroviral therapy.

OBJECTIVE: Self-report of antiretroviral medications adherence is inexpensive and simple to use in clinical settings but grossly overestimates adherence. We investigated methods to calibrate patients' self-reported adherence to match objectively measured adherence more closely for the purpose of developing a practical and more accurate self-reported adherence measure. DESIGN: Longitudinal cohort design. METHODS: Using data from 2 prospective longitudinal clinical investigations conducted at 5 HIV clinics, we examined the discrepancy between self-reported adherence and objectively measured adherence. We evaluated the relation between attitudinal measures and the degree of discrepancy and used a cross-validation approach to propose candidate items to improve adherence survey methodology. RESULTS: Among 330 patients, self-reported adherence was consistently higher than objectively measured adherence. The best calibration models included the patient's self-reported adherence, duration of the antiretroviral regimen, and attitudinal measures (ability to take medication as instructed, believing medication can help one to live longer, whether or not it is too troublesome to take antiretrovirals, and feeling things are going the right way). CONCLUSION: The method efficiently identified survey items to improve self-reported adherence measurement. The calibrated measure more closely approximates objectively measured adherence and is more sensitive for detecting nonadherence. These models merit evaluation in other settings.

Adult↗

PubMed2006

A pilot study of health beliefs and attitudes concerning measures of antiretroviral adherence among prisoners receiving directly observed antiretroviral therapy.

High level adherence to antiretroviral therapy (ART) is required to achieve and maintain suppression of HIV replication. Although directly observed therapy (DOT) has been suggested as an intervention to improve adherence, there is a paucity of data describing the attitudes and beliefs regarding DOT for ART among HIV-infected individuals. This study was designed to evaluate the acceptability and psychometric properties of a survey instrument for use in assessing barriers and facilitators of adherence to ART DOT in prison. From July 1, 1999 to April 1, 2000, we piloted an interviewer-administered questionnaire to assess health beliefs and attitudes regarding HIV treatment among 65 HIV-infected prison inmates receiving one or more of their antiretrovirals via directly observed therapy (DOT). The first 24 participants were administered the questionnaire to determine the feasibility of surveying prisoners in a correctional setting. There were no adherence data collected on these participants. The remaining 41 participants had their adherence measured in addition to receiving the questionnaire. Thirty-one were included in the final analysis because 10 did not complete the study. Multiple antiretroviral adherence measures (electronic device medication monitoring [eDEM] caps, medication administration records [MARs], and pill counts) were assessed among a subset of the participants (n = 31) and correlated to the instrument response items. The median internal consistency reliability coefficient for the multi-item scales was 0.79. The strongest correlation between inmates' beliefs and their adherence was between "positive beliefs about protease inhibitors" and the MAR adherence measure (r = 0.72; p < 0.001). This study provides preliminary support for the psychometric properties of the survey in this correctional setting.

Anti-Retroviral Agents↗

PubMed2006

A comprehensive evaluation of survey questions for adherence to antiretroviral medications and exploratory analyses for identifying optimal sets of survey questions.

Although many methods for assessing adherence have been developed, most are not feasible for busy clinical settings. Using patients from the Adherence and Efficacy of Protease inhibitor Therapy (ADEPT) study (1998-2000), we systematically evaluated the relationship between psychosocial, environmental, clinical, and other factors with adherence to create composite variables (CVs) that are efficient with high sensitivity for detecting nonadherence and great potential for busy clinics. Eligible patients were protease inhibitor naïve or started a regimen within 3 months from baseline. Of the 128 patients who responded to survey at baseline, weeks 8, 24, and/or 48, mean (standard deviation [SD]) age was 39.3 (8.2) years with 81% male. About half of the patients were Latino, followed by 28% African American and 14% Caucasian. Sixteen percent reported injection drug use, and 40% had male-male sex. Mean CD4 count was 184.8 cells/mm(3) with a range from 1 to 1130 cells/mm(3). Thirty-two variables had a significant association with adherence at one or two time points and 9 were significantly associated with adherence over time. Among these significant factors, 8 also had a relationship with a clearly monotonic trend, by which 219 CVs were formed. Among these CVs, 8 were significantly associated with adherence and had a relationship with monotonic trend. Compared to traditional self-reported adherence, CVs had much higher sensitivities (p < 0.001) for detecting nonadherence. We conclude that CVs consisting of a combination of psychological, behavior, and adherence questions may be reasonable substitutes for direct adherence questions, which are limited by problems with recall and social biases. Trust in physicians, having a child, history of substance use, CD4 count, and belief that antiretrovirals can help living longer or improve quality of life can efficiently predict nonadherence. Because these variables are readily obtainable in clinical settings, these selected questions may provide a clinically useful means of screening patients for antiretroviral medication nonadherence.

Adult↗

PubMed2006

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 1,105 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.

Adolescent↗

PubMed2006

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.

Adult↗

PubMed2006

Sexual behaviours of HIV-seropositive men and women following release from prison.

Twenty-five percent of the US HIV-infected population is released from a prison or jail each year. As the extent of risky sexual behaviours after prison release is largely unknown, we interviewed a cohort (n = 64) of HIV-infected, recently released (mean 45 days, SD 28) prisoners about their current sexual risk behaviours. Almost half (47%, n = 64) of the released prisoners reported sexual activity after release, mostly with regular partners. Although 26% (n = 27) reported engaging in unprotected sexual activity with their regular partners, none (n = 4) reported unprotected sex with their non-regular partners. Furthermore, 33% percent (n = 15) of the releasees with regular partners reported engaging in unprotected sex with HIV-seronegative partners. These results suggest that regular partners of HIV-infected prison releasees are at risk of acquiring HIV infection, and secondary risk-reduction strategies are needed for HIV-infected prison releasees.

Adult↗

PubMed2006

HIV and incarceration: dual epidemics.

As a result of changes in the epidemiology of the HIV epidemic and in criminal justice policies over the past 2 decades, HIV infection in the United States has become concentrated in prisons and jails. The widespread incarceration of persons with or at risk for HIV infection has important public health ramifications, including but not limited to the intraprison spread of the virus. Incarceration, particularly of large numbers of men, can be socially disruptive and , in communities where incarceration is prevalent, can facilitate the spread of HIV infection. Interventions to enhance identification of infected inmates, prevention counseling, and treatment of inmates with HIV/AIDS are required to stem the contribution of incarceration to the spread of HIV infection.

Adult↗

PubMed2005

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.

Dimerization↗

PubMed2005

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.

Adolescent↗

PubMed2005

HIV and stigma: analysis and research program.

Despite advances in our understanding of HIV transmission and optimal treatment of people with HIV infection, stigmatizing attitudes are a significant barrier to HIV prevention and treatment. Several studies demonstrate that stigma directed towards people with HIV infection presents an obstacle to getting tested for HIV, obtaining optimal HIV care, and engaging in safe sex practices. We review the literature on individual and societal factors associated with HIV-associated stigma and propose a framework for intervention design.

Attitude to Health↗

PubMed2005

Ordered processing of the human immunodeficiency virus type 1 GagPol precursor is influenced by the context of the embedded viral protease.

Ordered and accurate processing of the human immunodeficiency virus type 1 (HIV-1) GagPol polyprotein precursor by a virally encoded protease is an indispensable step in the appropriate assembly of infectious viral particles. The HIV-1 protease (PR) is a 99-amino-acid enzyme that is translated as part of the GagPol precursor. Previously, we have demonstrated that the initial events in precursor processing are accomplished by the PR domain within GagPol in cis, before it is released from the polyprotein. Despite the critical role that ordered processing of the precursor plays in viral replication, the forces that define the order of cleavage remain poorly understood. Using an in vitro assay in which the full-length HIV-1 GagPol is processed by the embedded PR, we examined the effect of PR context (embedded within GagPol versus the mature 99-amino-acid enzyme) on precursor processing. Our data demonstrate that the PR domain within GagPol is constrained in its ability to cleave some of the processing sites in the precursor. Further, we find that this constraint is dependent upon the presence of a proline as the initial amino acid in the embedded PR; substitution of an alanine at this position produces enhanced cleavage at additional sites when the precursor is processed by the embedded, but not the mature, PR. Overall, our data support a model in which the selection of processing sites and the order of precursor processing are defined, at least in part, by the structure of GagPol itself.

Binding Sites↗

PubMed2004

No evidence of an association between transient HIV viremia ("Blips") and lower adherence to the antiretroviral medication regimen.

BACKGROUND: Transient human immunodeficiency virus (HIV) viremia, a common phenomenon among patients taking antiretroviral therapy, is often attributed to lapses in adherence to the medication regimen. We investigated this relationship in a prospective observational cohort of 128 patients initiating a new regimen. METHODS: A case of transient viremia was defined as an HIV RNA level of 40-1000 copies/mL ("blip") sandwiched between 2 months of HIV RNA levels <40 copies/mL ("pre" and "post"). Adherence was most often measured with a composite adherence score (CAS), which is primarily based on electronically measured adherence. Case subjects' adherence and dose-timing was compared with (1) that of other patients (control subjects), who had undetectable virus loads for 3 consecutive months, and (2) that during periods of sustained undetectable virus loads among the case subjects themselves, if available. RESULTS: Among the 28 case subjects, mean CAS-measured adherence did not decrease before transient viremia; adherence during the pre, blip, and post periods were 86%, 84%, and 80%, respectively. Control subjects had lower adherence levels during the corresponding 3 months (77%, 79%, and 75%, respectively; P = .046). Among the 19 patients able to serve as their own controls, CAS-measured adherence was higher during the period of transient viremia than during control periods (P = .01). Similar relationships were found when comparing only electronically measured adherence on a week-wise basis. There were no significant differences in dose-timing error between case subjects and control subjects. CONCLUSIONS: We found no evidence that transient HIV viremia is associated with decreases in adherence or differences in dose-timing. Other etiologies for transient viremia should be evaluated.

Adult↗

PubMed2004

Predictors of repeat testing and HIV seroconversion in a sexually transmitted disease clinic population.

OBJECTIVE: This study assessed the extent of and characteristics associated with repeat HIV testing in persons presenting to a sexually transmitted disease (STD) clinic. METHODS: The study population included all 101 newly diagnosed HIV-infected subjects and 411 matched HIV-uninfected subjects identified over a 5-year period in a publicly funded STD clinic in the southeastern United States. RESULTS: Of the 508 subjects (99%) with available records, 160 (32%) had tested previously. Age, race, return for posttest counseling, and the client's stated reason for coming to the clinic were associated with repeat testing. Among the 160 subjects who had tested previously, self-identifying as a man who has sex with men or having a history of incarceration was strongly associated with HIV seroconversion (adjusted odds ratio [OR], 51.82; 95% confidence interval [CI], 9.10-295.13; adjusted OR, 83.98, 95% CI, 17.26-408.69, respectively). Presenting for STD-related reasons (STD symptoms or requesting an STD check) had a negative association with HIV seroconversion (adjusted OR, 0.07; 95% CI, 0.01-0.90) compared with presenting for the sole purpose of requesting an HIV test. CONCLUSIONS: Repeat HIV testing is common among patients receiving services at an STD clinic. The role of repeat testing in HIV prevention efforts is complex and poorly understood. Results from this study could be used to identify and target those testing previously at highest risk for contracting HIV for risk-reduction interventions.

AIDS Serodiagnosis↗

PubMed2004

Initial cleavage of the human immunodeficiency virus type 1 GagPol precursor by its activated protease occurs by an intramolecular mechanism.

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.

Animals↗

PubMed2004

Availability of and access to medical services among HIV-infected inmates incarcerated in North Carolina county jails.

This study assessed human immunodeficiency virus (HIV)-related services in county jails and staff perceptions of HIV-infected inmates and their care. A statewide telephone questionnaire was administered to detention officers and health care workers providing medical services in North Carolina jails. Eighty-five percent of participating facilities employed one or more on-site medical personnel, including physicians (51%), physician assistants (14%), and nurses (71%). Only 25% of jails tested more than one inmate for HIV per month. In 75% of jails, initial medical screening was performed in a common area. Officers administered medical screening forms at 93% of jails and distributed medications at 81%. Ninety-three percent of officers and 94% of medical staff agreed with this statement: "If an inmate is taking medications in jail, other inmates will know about it." Overall, our data indicate that few North Carolina jail inmates are tested for HIV. Greater protection of confidentiality may improve screening and treatment of HIV-infected inmates.

Anti-Retroviral Agents↗

PubMed2003

Adherence to directly observed antiretroviral therapy among human immunodeficiency virus-infected prison inmates.

Directly observed therapy (DOT) for human immunodeficiency virus (HIV) infection is commonly used in correctional settings; however, the efficacy of DOT for treating HIV infection has not been determined. We prospectively assessed adherence to antiretroviral therapy regimens among 31 HIV-infected prison inmates who were receiving >or=1 antiretrovirals via DOT. Adherence was measured by self-report, pill count, electronic monitoring caps, and, for DOT only, medication administration records. Overall, median adherence was 90%, as measured by pill count; 86%, by electronic monitoring caps; and 100%, by self-report. Adherence, as measured by electronic monitoring caps, was >90% in 32% of the subjects. In 91% of cases, adherence, as measured by medication administration records, was greater than that recorded by electronic monitoring caps for the same medications administered by DOT. Objective methods of measurement revealed that adherence to antiretroviral regimens administered wholly or in part by DOT was <or=90% in more than one-half of the patients. Different methods used to measure adherence revealed significantly different levels of adherence. These findings suggest that use of DOT does not ensure adherence to antiretroviral therapy.

Adult↗

PubMed2003

Mutagenesis of the dimer interface residues of tethered and untethered HIV-1 protease result in differential activity and suggest multiple mechanisms of compensation.

As is the case for all retroviruses, the protease of HIV-1 is only functional as a homodimer; dimerization of two protease monomers results in the formation of the enzyme active site. This dimer structure is supported primarily by interactions between the first four amino-terminal and the last four carboxy-terminal amino acids. These eight amino acids form a beta-sheet in which hydrophobic residues are oriented towards the core of the molecule and polar residues are directed towards the solvent. Although the structure of the dimer interface has been determined, the forces that support dimerization have not been fully characterized. Here, we describe a tethered construct in which two protease monomers are joined by a 5 amino acid linker. We evaluate the relative role of each dimer interface residue in functional homo- and heterodimers. Our studies indicate that the hydrophobic residues of the dimer interface are particularly important in maintaining enzyme activity and that enzyme activity is more sensitive to substitutions of the C-terminal amino acids. Further, we demonstrate that the presence of the tether is able to compensate for mutations within the dimer interface that inactivate the enzyme.

Amino Acid Substitution↗