Effect of directly observed antiretroviral therapy compared to self-administered antiretroviral therapy on adherence and virological outcomes among HIV-infected prisoners: a randomized controlled pilot study.

The effect of directly observed therapy (DOT) versus self-administered therapy (SAT) on antiretroviral (ART) adherence and virological outcomes in prison has never been assessed in a randomized, controlled trial. Prisoners were randomized to receive ART by DOT or SAT. The primary outcome was medication adherence [percent of ART doses measured by the medication event monitoring system (MEMS) and pill counts] at the end of 24 weeks. The changes in the plasma viral loads from baseline and proportion of participants virological suppressed (<400 copies/mL) at the end of 24 weeks were assessed. Sixty-six percent (90/136) of eligible prisoners declined participation. Participants in the DOT arm (n = 20) had higher viral loads than participants in the SAT (n = 23) arm (p = 0.23). Participants, with complete data at 24 weeks, were analyzed as randomized. There were no significant differences in median ART adherence between the DOT (n = 16, 99% MEMS [IQR 93.9, 100], 97.1 % pill count [IQR 95.1, 99.3]) and SAT (n = 21, 98.3 % MEMS [IQR 96.0, 100], 98.5 % pill count [95.8, 100]) arms (p = 0.82 MEMS, p = 0.40 Pill Count) at 24 weeks. Participants in the DOT arm had a greater reduction in viral load of approximately -1 log 10 copies/mL [IQR -1.75, -0.05] compared to -0.05 [IQR -0.45, 0.51] in the SAT arm (p value = 0.02) at 24 weeks. The proportion of participants achieving virological suppression in the DOT vs SAT arms was not statistically different at 24 weeks (53 % vs 32 %, p = 0.21). These findings suggest that DOT ART programs in prison settings may not offer any additional benefit on adherence than SAT programs.

HIV-1 protease function and structure studies with the simplicial neighborhood analysis of protein packing method.

The Simplicial Neighborhood Analysis of Protein Packing (SNAPP) method was used to predict the effect of mutagenesis on the enzymatic activity of the HIV-1 protease (HIVP). SNAPP relies on a four-body statistical scoring function derived from the analysis of spatially nearest neighbor residue compositional preferences in a diverse and representative subset of protein structures from the Protein Data Bank. The method was applied to the analysis of HIVP mutants with residue substitutions in the hydrophobic core as well as at the interface between the two protease monomers. Both wild-type and tethered structures were employed in the calculations. We obtained a strong correlation, with R(2) as high as 0.96, between DeltaSNAPP score (i.e., the difference in SNAPP scores between wild-type and mutant proteins) and the protease catalytic activity for tethered structures. However, a weaker but significant correlation was obtained for nontethered structures. Our analysis identified residues both in the hydrophobic core and at the dimeric interface that are very important for the protease function. This study demonstrates a potential utility of the SNAPP method for rational design of mutagenesis studies and protein engineering.

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.

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.

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.

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.

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.

Effect of release from prison and re-incarceration on the viral loads of HIV-infected individuals.

OBJECTIVES: The purpose of this study was to determine the effect of release from prison and subsequent re-incarceration on the viral loads of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). METHODS: Fifteen re-incarcerated HIV-infected prisoners on HAART were identified from a retrospective cohort of HIV-infected prison inmates released from January 1, 1997, to August 31, 1999. The re-incarcerated prisoners were matched (1:2) to 30 HIV-infected incarcerated prisoners on HAART who remained incarcerated during the re-incarcerated participants' release time period. The outcomes measured were plasma HIV RNA levels, CD4+ lymphocyte counts, percentage of re-incarcerated and incarcerated participants with plasma HIV RNA levels <400 copies/mL, and the median change in plasma HIV RNA levels of the re-incarcerated and incarcerated participants at the end of the study. RESULTS: At the beginning of the study, 8/15 re-incarcerated participants had plasma HIV RNA levels <400 copies/mL, compared with 15/30 incarcerated participants. At the end of the study, only three of those eight re-incarcerated participants had plasma HIV RNA levels <400 copies/mL, compared with 14/15 incarcerated participants (p=0.0086). The median change in plasma HIV RNA levels of the re-incarcerated participants was 1.29 log10 copies/mL (interquartile range 0.04 to 1.70), compared with -0.03 log10 copies/mL (interquartile range -0.65 to 0.09) in the incarcerated participants (p=0.0183). CONCLUSIONS: Release from prison was associated with a deleterious effect on virological and immunological outcomes. These data suggest that comprehensive discharge planning efforts are required to make certain that HIV-infected inmates receive access to quality care following incarceration.

Assembly of the HIV-1 core particle.

The core particle of HIV-1 assembles at the membrane of the host cell as the virus buds from the surface. The structural proteins and enzymes that comprise the core are translated as part of two polyprotein precursors, Gag and GagPol. The Gag precursor contains the structural proteins of the core and is both necessary and sufficient for directing particle assembly and budding. Over the past few years, significant progress has been made in our understanding of the interactions that drive particle assembly. Specifically, determinants within the Gag precursor that direct membrane association, Gag-Gag interactions and particle budding have been identified and partially characterized. Subdomains of the host cell membrane that favor particle assembly and budding have also been described. Finally, a potential role for cellular processes in mediating the final stages in particle release has recently been proposed and a cellular protein that appears to bind directly to the Gag precursor has been identified. Each of these observations helps to clarify previously obscure aspects of viral replication and points towards potential targets for the design of novel therapies.

Knowledge of antiretroviral regimen dosing and adherence: a longitudinal study.

In a cohort of 128 human immunodeficiency virus-infected patients, we found that patients' knowledge of antiretroviral dosing was suboptimal at regimen initiation but improved with time. Poor medication knowledge 8 weeks after regimen initiation was associated with lower adherence and with a lower level of literacy in a multivariate model (P=.03). Because knowledge deficits are common after antiretroviral regimen initiation, clinicians should assess patients' understanding of medication dosing soon after regimen initiation or change.

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

Bootstrap confidence levels for HIV-1 recombination.

Recombination has been invoked to explain the disparate evolutionary relationships observed for different genes or sequence segments of a single HIV-1 genome. We present a new method of assessing confidence in HIV-1 recombination as an alternative to the segment-by-segment nonparametric bootstrap commonly applied to confirm HIV-1 recombinant data. Our new method uses the bias-corrected accelerated percentile interval (BCa) bootstrap method as applied to the "problem of regions" (Efron and Tibshirani 1998). It is an extension of the BCa method used in the inference of evolutionary relationships (Efron et al. 1996). This method has two advantages over the traditional bootstrap procedure: (1) it gives a single overall confidence measure rather than segment-by-segment results, and (2) it is more accurate. We test our method on 61 sequences, including 16 with ambiguous recombinant status.

Impact of antiretroviral regimen switches on adherence.

PURPOSE: An understanding of the situations in which adherence lapses occur is critical to the design of effective interventions to enhance adherence. We investigated whether a switch in antiretroviral medications affected adherence by examining a prospective observational cohort of 128 patients who began a new antiretroviral regimen. METHOD: Adherence was measured using electronic devices, pill counts, and self-reports, which were combined into a composite adherence measure and expressed as the proportion of prescribed medication taken. RESULTS: During 1,056 person-months of follow-up, 129 medication regimen changes occurred among 84 patients (66% of participants). Among the 89 analyzable switches (representing 66 patients), the most common reasons for switch included pill to liquid ritonavir (n = 26), gastrointestinal intolerance (n = 11), virologic failure (n = 8), and peripheral neuropathy (n = 7). Overall, mean adherence prior to regimen switch exceeded mean adherence after regimen switch (0.75 vs. 0.70; p =.035). Among subgroups of switches, adherence decreased significantly after switching from pill to liquid ritonavir (0.83 vs. 0.68; p <.001). When this group was excluded, there was no change in adherence after switches (0.72 vs. 0.71; p =.74). CONCLUSION: Antiretroviral regimen changes are not associated with adherence improvement and may be associated with declining adherence when a new regimen is unpalatable. Antiretroviral regimen changes should trigger reassessment of adherence and, when appropriate, adherence intervention.

Failure to return for HIV posttest counseling in an STD clinic population.

This study assessed the extent of and characteristics associated with FTR for HIV posttest counseling in persons undergoing an HIV test during their visit to a sexually transmitted disease (STD) clinic. 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. Overall, 55% of subjects failed to return for their test results. HIV testing history, demographic characteristics, and STD diagnosis were associated with FTR. Of clients testing HIV-positive, 58% failed to return. A median of 12 days was required for disease intervention specialists (DIS) to locate HIV-infected subjects who failed to return. The proportion of persons returning for HIV antibody test results is low among patients tested while seeking STD services. Considerable time and effort is required to find and notify those subjects testing HIV-positive who fail to return. To maximize the potential benefit of counseling and testing, interventions need to be designed to target those at highest risk of not returning.

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.

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.

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.

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.

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.