Patient and provider perspectives on cellular phone-based technology to improve HIV treatment adherence.

Innovative techniques, potentially using technology, to improve adherence to antiretroviral therapy (ART) may help patients with HIV who struggle with self-care. This qualitative study compared patient and provider participants' perspectives on ART adherence and text messaging as a tool to promote adherence. Thirteen providers and 14 HIV-infected patients identified four main themes: (1) facilitators, (2) barriers to using text message reminders as a medium for ART medication reminders, (3) framing of text message reminders, and (4) patient responsibility and autonomy in the management of their health and wellness. Ease of use, access, convenience, and confidentiality were cited as benefits of a text message-based adherence intervention; while access, cost, difficulty manipulating cellular phones, lack of knowledge/education, and confidentiality were cited as potential barriers. Providers, but not patients, also identified patient apathy and time burden as potential barriers to a text message-based adherence reminder system. Patients and providers felt that personalization of messages, attention to timing, and confidentiality of messages were key factors for a successful text message-based adherence reminder system. Both providers and patients felt that patient responsibility and autonomy over an individual's own health care is an important issue in adherence to medical care. The majority of patients and providers felt that a text message-based adherence reminder system would be beneficial. While patients and providers had many similar views on factors influencing adherence with ART and the use of text messaging to improve adherence, there were some divergent views between the two groups.

A low-effort, clinic-wide intervention improves attendance for HIV primary care.

BACKGROUND: Retention in care for human immunodeficiency virus (HIV)-infected patients is a National HIV/AIDS Strategy priority. We hypothesized that retention could be improved with coordinated messages to encourage patients' clinic attendance. We report here the results of the first phase of the Centers for Disease Control and Prevention/Health Resources and Services Administration Retention in Care project. METHODS: Six HIV-specialty clinics participated in a cross-sectionally sampled pretest-posttest evaluation of brochures, posters, and messages that conveyed the importance of regular clinic attendance. 10,018 patients in 2008-2009 (preintervention period) and 11,039 patients in 2009-2010 (intervention period) were followed up for clinic attendance. Outcome variables were the percentage of patients who kept 2 consecutive primary care visits and the mean proportion of all primary care visits kept. Stratification variables were: new, reengaging, and active patients, HIV RNA viral load, CD4 cell count, age, sex, race or ethnicity, risk group, number of scheduled visits, and clinic site. Data were analyzed by multivariable log-binomial and linear models using generalized estimation equation methods. RESULTS: Clinic attendance for primary care was significantly higher in the intervention versus preintervention year. Overall relative improvement was 7.0% for keeping 2 consecutive visits and 3.0% for the mean proportion of all visits kept (P < .0001). Larger relative improvement for both outcomes was observed for new or reengaging patients, young patients and patients with elevated viral loads. Improved attendance among the new or reengaging patients was consistent across the 6 clinics, and less consistent across clinics for active patients. CONCLUSION: Targeted messages on staying in care, which were delivered at minimal effort and cost, improved clinic attendance, especially for new or reengaging patients, young patients, and those with elevated viral loads.

A practical guide to vaccinating the inflammatory bowel disease patient.

The increasing use of corticosteroids, immune modulators, and biologics as a mainstay of therapy in certain Crohn's disease and ulcerative colitis patients have placed these inflammatory bowel disease (IBD) patients at increased risk for a variety of infections, many of which are preventable by prior vaccination. This article provides a review of the issues surrounding immunizations in the IBD patient and a practical guide for clinicians regarding the appropriate vaccinations to administer both before and during immunosuppressive therapy.

Response to vicriviroc in treatment-experienced subjects, as determined by an enhanced-sensitivity coreceptor tropism assay: reanalysis of AIDS clinical trials group A5211.

The enhanced-sensitivity Trofile assay (Monogram Biosciences) was used to retest coreceptor use at both study screening and study entry for 118 treatment-experienced subjects in AIDS Clinical Trials Group A5211 who had CCR5-tropic (R5) virus detected by the original Trofile assay at study screening. Among 90 recipients of vicriviroc, a significantly (P< .001) greater mean reduction in HIV-1 RNA was observed in 72 subjects with R5 virus versus 15 subjects reclassified as having dual/mixed-tropic viruses at screening: -1.11 versus -0.09 log(10) copies/mL at day 14 and -1.91 versus -0.57 log(10) copies/mL at week 24, respectively. Results suggest that the enhanced-sensitivity assay is a better screening tool for determining patient eligibility for CCR5 antagonist therapy.

Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384.

BACKGROUND: Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized. METHODS: Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4(+), CD4(+) naive and memory, CD4(+) activation, CD8(+), CD8(+) activation, B, and natural killer cells among patients in different baseline CD4(+) strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113. RESULTS: Patients in the lower baseline CD4(+) strata did not achieve total CD4(+) cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4(+) cell count increases were similar. Ratios of CD4(+) naive-memory cell counts and CD4(+):CD8(+) cell counts remained significantly reduced in patients with lower baseline CD4(+) cell counts (350 cells/mm(3) achieved or approached the reference range those of control individuals without HIV infection. In contrast, patients who began ART with

Lymphoma diagnosis and plasma Epstein-Barr virus load during vicriviroc therapy: results of the AIDS Clinical Trials Group A5211.

BACKGROUND: Lack of functional CCR5 increases the severity of certain viral infections, including West Nile virus and tickborne encephalitis. In a phase II trial of the investigational CCR5 antagonist vicriviroc (AIDS Clinical Trials Group protocol A5211), 4 lymphomas occurred in study patients who received vicriviroc. Because of the known association between unregulated Epstein-Barr virus (EBV) replication and lymphoma in immunocompromised patients, we evaluated whether vicriviroc exposure was associated with lymphoma EBV antigen positivity and/or had an effect on plasma levels of EBV DNA. METHODS: Clinical findings for all 4 patients enrolled in the A5211 study who developed lymphoma (2 Hodgkin and 2 non-Hodgkin) were reviewed, and tumor specimens were assessed for evidence of ongoing EBV replication. Longitudinal plasma samples from 116 patients in the A5211 study were analyzed, and EBV DNA was quantified by real-time polymerase chain reaction. RESULTS: Plasma EBV DNA was not detected in the 2 patients with non-Hodgkin lymphoma; both patients with Hodgkin lymphoma who had samples tested had EBV DNA levels <3200 copies/mL. One patient with Hodgkin lymphoma had a lymph node core biopsy specimen that was strongly positive for EBV; the other 3 lymphomas were histochemically EBV negative. None of the 116 patients with available samples experienced sustained increases in plasma EBV levels. CONCLUSIONS: CCR5 antagonism by vicriviroc treatment in treatment-experienced patients was not associated with reactivation of EBV infection.

Assessing human immunodeficiency virus type 1 tropism: Comparison of assays using replication-competent virus versus plasma-derived pseudotyped virions.

Detection of CXCR4-using human immunodeficiency virus by the Trofile assay was compared to that by assays using virus isolates or replication-competent recombinants. Concordance with the Trofile assay was good, but assays using replicating viruses did not increase substantially the ability to detect the presence of CXCR4-using virus.

Human immunodeficiency virus infection alters tumor necrosis factor alpha production via Toll-like receptor-dependent pathways in alveolar macrophages and U1 cells.

Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-alpha) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-alpha activity, as measured by the TNF-alpha/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-alpha is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-alpha production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam(3)Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-alpha in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-alpha production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

Patient risks, outcomes, and costs of voluntary HIV testing at five testing sites within a medical center.

OBJECTIVES: The Centers for Disease Control and Prevention (CDC) recommends offering human immunodeficiency virus (HIV) testing to all patients in all high HIV-prevalence clinical settings. We evaluated programmatic aspects of HIV testing across multiple clinical settings within a single medical center. METHODS: We analyzed programmatic data of HIV testing in the Urgent Care Center (UCC), inpatient floors, outpatient primary care, a non-clinical Drop-In Center, and Emergency Department (ED). HIV testing was by oral mucosal transudate, venous blood samples, or rapid testing fingersticks, with Western blot confirmation. We compared the sociodemographics and behavioral risks of individuals undergoing HIV testing across the five sites and estimated costs per person tested and per HIV-positive test result. RESULTS: From 2002 to 2004, 16,750 HIV tests were conducted, with 229 (1.4%) previously unreported HIV infections diagnosed among 16,696 valid test results. HIV-positive prevalence was 1.5% for the UCC, 1.5% at the Drop-In Center, 1.4% for primary care, 1.2% for inpatient, and 0.6% in the ED. Behavioral risks were most prevalent in the UCC and the Drop-In Center. The cost per test was lowest in the UCC and highest in the Drop-In Center. The cost per previously unreported HIV infection was lowest in the UCC ($1,980) and highest in the ED ($9,724). CONCLUSIONS: Although a significant number of HIV infections were identified, the number of tests performed represents < 10% of all clinical visits. Due to personnel and time constraints, offering HIV testing to patients hierarchically in some settings of a high-volume medical center merits evaluation.

HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211.

BACKGROUND: Chemokine coreceptor use impacts both the natural history of human immunodeficiency virus type 1 (HIV-1) disease and the potential use of a new class of antiretroviral agents, the CCR5 inhibitors. METHODS: We analyzed HIV-infected patients who were screened for participation in Acquired Immunodeficiency Syndrome (AIDS) Clinical Trial Group protocol A5211, a phase 2b study of the investigational CCR5 inhibitor vicriviroc involving antiretroviral-experienced subjects. Screening CD4(+) cell count, HIV-1 plasma RNA level, HIV-1 genotype, and chemokine coreceptor use phenotype were determined. The univariate and multivariate association of subject characteristics with coreceptor use was assessed by logistic regression. RESULTS: Coreceptor use was determined for 391 subjects: 197 (50%) had virus that used the CCR5 coreceptor (the R5 group), 178 [corrected] (46%) had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4 coreceptors (the D/M group), and 16 (4%) had virus that used the CXCR4 coreceptor (the X4 group). The D/M group had a significantly lower median CD4(+) cell count than the R5 virus group (103 cells/ micro L vs. 170 cells/ mu L; P<.001). No other characteristics were independently associated. Among 118 subjects who entered A5211 having R5 virus, 12 (10%) had D/M virus according to the results of a second coreceptor test conducted prior to starting treatment with the study drug. CONCLUSIONS: Infection with dual-tropic or mixed HIV-1 populations that use both CCR5 and CXCR4 is common among highly treatment-experienced patients, but infection with virus using CXCR4 alone is uncommon. Subjects in the D/M group had significantly lower CD4(+) cell counts than subjects in the R5 group. Evaluating coreceptor use will be important in the clinical development of CCR5 and CXCR4 inhibitors.

Effect of a four-week course of interleukin-10 on cytokine production in a placebo-controlled study of HIV-1-infected subjects.

Interleukin (IL)-10 suppresses synthesis of the pro-inflammatory cytokines tumor necrosis factor (TNF)alpha, IL-1beta, and interferon (IFN)gamma. Since pro-inflammatory cytokines have been implicated in the production of human immunodeficiency virus type 1 (HIV-1), cytokine synthesis in whole blood cultures were determined during a 4-week course of subcutaneous IL-10 injections in 33 HIV-1-infected patients. Patients were randomized into four groups: placebo (nine), IL-10 at 1 microg/kg/day (nine), IL-10 at 4 microg/kg/day (six) and IL-10 at 8 microg/kg three times per week (nine). Whole blood was obtained at the beginning and conclusion of the study and was stimulated for 24 hours with the combination of IL-18 plus lipopolysaccharide. TNFalpha production in stimulated whole blood was reduced three and six hours after the first injection of IL-10 compared to subjects injected with the placebo. After four weeks of treatment, production of IFNgamma was suppressed in a greater number of patients in the IL-10 treatment groups compared to subjects in the placebo group. Similarly, IL-1beta production was lower in the IL-10 treatment groups compared to subjects receiving placebo. In contrast, after four weeks of IL-10, circulating levels of the anti-inflammatory TNF soluble receptor p55 increased dose-dependently compared to placebo subjects. Patient heterogeneity and small sample size presented difficulties in establishing statistical significance. Although the cytokine changes in our study did not demonstrate statistically significant changes, the data nevertheless reveal that four weeks of IL-10 therapy in HIV-1 infected subjects produced the anticipated suppression of pro-inflammatory cytokines.

Evaluation of the Centers for Disease Control and Prevention's recommendations regarding routine testing for human immunodeficiency virus by an inpatient service: who are we missing?

OBJECTIVE: To assess the proportion of hospitalized patients who tested positive for human immunodeficiency virus (HIV) by a routine inpatient testing service, as recommended by the Centers for Disease Control and Prevention, who might not have been identified had routine testing not been offered. PATIENTS AND METHODS: In this retrospective cohort study, the medical records of patients who tested HIV positive by the inpatient testing service between 1999 and 2003 were compared with the medical records of inpatients who tested HIV negative by the inpatient testing service and the medical records of patients who tested HIV positive in ambulatory settings. We compared HIV risk factors, discharge diagnoses, CD4 cell counts, and HIV RNA concentrations. RESULTS: A total of 243 patients participated in this study: 81 patients who tested HIV positive and 81 who tested HIV negative by the inpatient testing service, and 81 patients who tested HIV positive in ambulatory settings. Both HIV-positive inpatients and HIV-positive outpatients had similar frequencies of HIV risk factors (46% vs 43%; P=.75). Both groups differed significantly from HIV-negative inpatients (4%; P<.001). Comparing HIV-positive inpatients with HIV-positive outpatients, CD4 cell counts were lower (196 vs 371 cells/mm3; P<.001), and HIV RNA levels were higher (4.61 vs 4.09 Iog, HIV RNA; P=.001). At diagnosis, 64 HIV-positive inpatients (79%) met criteria for acquired immunodeficiency syndrome compared with 21 HIV-positive outpatients (26%) (P<.001). CONCLUSION: Patients who tested HIV positive through inpatient testing have more advanced disease than those identified as outpatients. Half of these patients would not have been identified had testing not been routinely offered. Routine inpatient HIV testing offers an important opportunity to identify patients with HIV infection.

Approaching the CDC's guidelines on the HIV testing of inpatients: physician-referral versus nonreferral-based testing.

Despite ongoing evidence that one quarter of HIV-infected people in the United States are unaware of their infection, widespread implementation of the Centers for Disease Control and Prevention's 1993 recommendations regarding routine inpatient HIV testing has not occurred. This study compares two HIV testing strategies: the initial phase of inpatient HIV testing (1999-2001) utilized a physician-referral-based system. The second phase (2001-2003) included the first 2 years' experience with having trained HIV counselors directly approach inpatients regarding their willingness to undergo voluntary HIV counseling and testing (VCT) without physician referral. This latter phase was prompted by a patient attitude survey demonstrating favorable responses to unsolicited approaches by staff regarding HIV testing. Barriers to implementing the latter strategy are discussed and initial experience with rapid HIV testing on this service is also presented. Referral-based testing yielded 2.3 patient referrals (6.4% of total admissions) resulting in 1.2 HIV tests and 0.7 counseling only sessions per day. Nonreferral based testing resulted 6.2 HIV tests and another 3.0 counseling-only sessions per day. HIV VCT on an inpatient service is feasible but challenging. Most patients respond favorably to being approached for VCT. Routinely offering HIV tests to inpatients yields higher testing rates than physician referral-based systems and increases the number of patients who know their HIV status. Recommendations for implementing routing HIV testing on an inpatient service are made.

Highly active antiretroviral therapy and viral response in HIV type 2 infection.

Human immunodeficiency virus type 2 (HIV-2), the second human retrovirus known to cause AIDS, is endemic to West Africa but is infrequently found outside this region. We present a case series of 10 HIV-2--infected individuals treated in the United States. Physicians applied the principles of highly active antiretroviral therapy (HAART), normally used in treating HIV type 1, with modifications considered appropriate for treating HIV-2. CD4+ cell count, HIV-2 virus load, and clinical status were found to correlate well, providing evidence that HIV-2 virus load is useful in managing treatment of patients with HIV-2 who are receiving therapy. However, HAART regimens with predicted efficacy for treatment of HIV type 1 infection are not as efficacious for treatment of HIV-2. Controlled clinical trials of HIV-2-infected patients receiving various HAART regimens are needed to provide therapeutic guidance to the medical community.

Enfuvirtide, a new fusion inhibitor for therapy of human immunodeficiency virus infection.

Enfuvirtide is the first fusion inhibitor to be approved by the Food and Drug Administration for the treatment of chronic human immunodeficiency virus (HIV) infection in adults and children 6 years and older. The drug is a synthetic peptide derived from a naturally occurring amino acid sequence known as heptad repeat 2 (HR2) found in gp41, a viral transmembrane glycoprotein that facilitates fusion with host cells. By mimicking the activity of HR2 and competitively binding to a second region of gp41, heptad repeat 1 (HR1), enfuvirtide prevents interaction between HR1 and HR2 and inhibits the conformational change of gp41 that is necessary for fusion of virions to host cells. The safety and efficacy of enfuvirtide have been studied only in antiretroviral-experienced persons. Preliminary data from two multicenter phase III clinical trials (T-20 versus Optimized Regimen Only [TORO 1, TORO 2]) suggest that the drug is safe and efficacious in heavily pretreated subjects through 24 weeks. By week 24, in TORO 1 and TORO 2, respectively, mean changes in HIV RNA concentrations of -1.7 and -1.4 log10 copies/ml were observed in subjects receiving enfuvirtide plus an optimized background (OB) regimen, compared with changes of -0.8 and -0.7 log10 copies/ml in subjects receiving an OB regimen alone. Resistance to enfuvirtide has been identified in vitro and in vivo. Most resistant variants contain mutations in the HR1 region of gp41 (positions 36-45). In phase III clinical trials, numerous substitutions within this critical region were associated with faster time to virologic failure over 24 weeks. Overall, enfuvirtide appears to be well tolerated and acceptable to patients despite a high rate of injection site reactions (> 90%). Bacterial pneumonia and eosinophilia occurred more frequently in subjects taking enfuvirtide than in those taking an OB regimen alone in phase III trials; however, no causal relationship was established. Like most drugs with peptide structures, enfuvirtide appears to have a low potential for metabolic drug-drug interactions. The approved dosage is 90 mg twice/day by subcutaneous injection in adults and 2 mg/kg twice/day in children older than 6 years. Enfuvirtide is an addition to antiretroviral therapy since it targets a new step in the HIV life cycle. Given the complexity of its production and administration, however, it is likely to be most useful in antiretroviral-experienced patients.

Clinical implications of elevated HIV-1 viral load results obtained from samples stored frozen in vacutainer plasma preparation tubes.

Studies have demonstrated that plasma samples collected and stored frozen using vacutainer plasma preparation tubes (PPT) may result in falsely elevated viral load (VL) values with the Roche COBAS TaqMan HIV-1 v1.0 test. At the University of Connecticut Health Center, a total of 349 samples from HIV-1-infected patients on HAART were collected and stored frozen in PPT. Viral load (VL) results were obtained using the Roche COBAS TaqMan HIV-1 v2.0 test (CTM v2.0) and Abbott RealTime HIV-1 assay (RealTime HIV-1). Of the 349 samples, 260 (74.5%) had VL values that differed by >0.5log10copies/mL; 64 of these were quantified by both assays. The remaining 196 samples were detected by CTM v2.0 but not detected in RealTime HIV-1: 62 of the most discordant samples in this category (CTM v2.0 detected/RealTime HIV-1 not detected) were further analyzed using two nested RT-PCR assays targeting pol integrase: full-length (864nt) and a highly conserved subregion (134nt). No HIV-1 RNA was detected in the discordant samples, confirming RealTime HIV-1 results. The increase in VL reactivity with the CTM v2.0 assay was presumably due to proviral DNA captured by the CTM total nucleic acid extraction chemistry but not the RNA-specific extraction procedure used in RealTime HIV-1. These results suggest that using CTM v2.0 with samples frozen in PPT could have significant clinical implications for HIV-1 patient management.

Development and field testing of an HIV medication touch screen computer patient adherence tool with telephone-based, targeted adherence counseling.

BACKGROUND: HIV medication nonadherence is a major problem, yet many providers lack the time and training to carefully ask patients about their adherence. OBJECTIVE: To design and pilot a technology-assisted intervention, for use in clinical settings, to identify nonadherent patients. METHODS: The intervention uses audio computer-assisted self-interview (ACASI) to improve the assessment of adherence and medication-related problems. Patients completed a touch screen computer ACASI which generated graphic clinician and patient reports for discussion during the clinical encounter. RESULTS: 72 patients and 11 providers participated in this study. The patients easily completed the ACASI. Adherence was 63% (3-day) and 47% (30-day). Using the ACASI, 22% of patients identified themselves as nonadherent, when their providers perceived them as adherent. CONCLUSIONS: This ACASI-based intervention is easy to use and helps identify nonadherence. The pilot test engendered enhancements including the addition of phone-based adherence counseling. A larger trial is underway to evaluate whether the intervention leads to improved HIV-related outcomes.

A collaborative awareness system for chronic disease medication adherence applied to HIV infection.

Electronic reminder systems have been available for decades, yet medication adherence remains poor. Most systems rely on simple alarms and do not address other determinants of health-related behavior. This paper describes a collaborative awareness system for chronic disease medication adherence that relies on patient self-reflection and clinician support. Visualizations of adherence performance, including estimated plasma concentration graphs and a dynamic, personalized, disease-state simulation, are available to the patient (cell phone and internet media display) and clinician (computer) in real-time. The clinician can send asynchronous video messages of advice and encouragement to the patient regularly. A pilot was conducted with four HIV positive patients for four weeks. Three patients who started with suboptimal adherence improved (93.0% to 99.1%, 83.0% to 96.3%, and 63.9% to 81.3%). One patient who started with optimal medication adherence (>95%) maintained this level. All four patients appreciated the rich feedback and wanted to continue using the system.