Low-Abundance HIV Drug-Resistant Viral Variants in Treatment-Experienced Persons Correlate with Historical Antiretroviral Use

BACKGROUND: It is largely unknown how frequently low-abundance HIV drug-resistant variants at levels under limit of detection of conventional genotyping (<20% of quasi-species) are present in antiretroviral-experienced persons experiencing virologic failure. Further, the clinical implications of low-abundance drug-resistant variants at time of virologic failure are unknown. METHODOLOGY/PRINCIPAL FINDINGS: Plasma samples from 22 antiretroviral-experienced subjects collected at time of virologic failure (viral load 1380 to 304,000 copies/mL) were obtained from a specimen bank (from 2004-2007). The prevalence and profile of drug-resistant mutations were determined using Sanger sequencing and ultra-deep pyrosequencing. Genotypes were interpreted using Stanford HIV database algorithm. Antiretroviral treatment histories were obtained by chart review and correlated with drug-resistant mutations. Low-abundance drug-resistant mutations were detected in all 22 subjects by deep sequencing and only in 3 subjects by Sanger sequencing. In total they accounted for 90 of 247 mutations (36%) detected by deep sequencing; the majority of these (95%) were not detected by standard genotyping. A mean of 4 additional mutations per subject were detected by deep sequencing (p<0.0001, 95%CI: 2.85-5.53). The additional low-abundance drug-resistant mutations increased a subject's genotypic resistance to one or more antiretrovirals in 17 of 22 subjects (77%). When correlated with subjects' antiretroviral treatment histories, the additional low-abundance drug-resistant mutations correlated with the failing antiretroviral drugs in 21% subjects and correlated with historical antiretroviral use in 79% subjects (OR, 13.73; 95% CI, 2.5-74.3, p = 0.0016). CONCLUSIONS/SIGNIFICANCE: Low-abundance HIV drug-resistant mutations in antiretroviral-experienced subjects at time of virologic failure can increase a subject's overall burden of resistance, yet commonly go unrecognized by conventional genotyping. The majority of unrecognized resistant mutations correlate with historical antiretroviral use. Ultra-deep sequencing can provide important historical resistance information for clinicians when planning subsequent antiretroviral regimens for highly treatment-experienced patients, particularly when their prior treatment histories and longitudinal genotypes are not available

An Analysis of Electronically Monitored Adherence to Antiretroviral Medications

Medication adherence studies increasingly collect data electronically, often using Medication Event Monitoring System (MEMS) caps. Analyses typically focus on summary adherence measures, although more complete analyses are possible using adaptive statistical methods. These methods were used to describe individual-subject adherence patterns for MEMS data from a clinical trial. Subjects were adaptively clustered into groups with similar adherence patterns and clusters were compared on a variety of subject characteristics. There were seven different adherence clusters: consistently high, consistently moderately high, consistently moderate, consistently moderately low, consistently low, deteriorating starting early, and deteriorating late. Compared to other subjects, subjects with consistently high and consistently moderately high adherence were more likely to be male, White, and older and to maintain during study participation a CD4 cell count over 500 and an HIV viral load of at most 400 copies/ml. These results demonstrate the effectiveness of adaptive methods for comprehensive analysis of MEMS data

An Analysis of Electronically Monitored Adherence to Antiretroviral Medications

Medication adherence studies increasingly collect data electronically, often using Medication Event Monitoring System (MEMS) caps. Analyses typically focus on summary adherence measures, although more complete analyses are possible using adaptive statistical methods. These methods were used to describe individual-subject adherence patterns for MEMS data from a clinical trial. Subjects were adaptively clustered into groups with similar adherence patterns and clusters were compared on a variety of subject characteristics. There were seven different adherence clusters: consistently high, consistently moderately high, consistently moderate, consistently moderately low, consistently low, deteriorating starting early, and deteriorating late. Compared to other subjects, subjects with consistently high and consistently moderately high adherence were more likely to be male, White, and older and to maintain during study participation a CD4 cell count over 500 and an HIV viral load of at most 400 copies/ml. These results demonstrate the effectiveness of adaptive methods for comprehensive analysis of MEMS data

Modeling HIV transmission from sexually active alcohol-consuming men in ART programs to seronegative wives

Background: The rollout of antiviral therapy in Low and Middle Income Countries (LMICs) has reduced HIV transmission rates at the potential risk of resistant HIV transmission. We sought to predict the risk of wild type and antiviral resistance transmissions in these settings. Methods: A predictive model utilizing viral load, ART adherence, genital ulcer disease, condom use, and sexual event histories was developed to predict risks of HIV transmission to wives of 233 HIV+ men in 4 antiretroviral treatment centers in Maharashtra, India. Results: ARV Therapy predicted a 5.71-fold reduction in transmissions compared to a model of using condoms alone, with 79.9%, of remaining transmissions resulting in primary ART-resistance. Conclusions: ART programs reduce transmission of HIV to susceptible partners at a substantial increased risk for transmission of resistant virus. Enhanced vigilance in monitoring adherence, use of barrier protections, and viral load may reduce risks of resistant HIV transmissions in LMIC settings

Bladder Cancer versus Hemorrhagic Cystitis: A Case of Mistaken Identity in a 34-Year-Old Male Undergoing Therapy for Granulomatosis with Polyangiitis

A 34-year-old male was referred for management of bladder cancer noted on workup for gross hematuria and new-onset irritative voiding symptoms. The patient\u27s history was significant for recently diagnosed granulomatosis with polyangiitis for which he was undergoing treatment with oral cyclophosphamide and corticosteroids. Cystoscopy revealed lesions suspicious for malignancy, but the patient was diagnosed with hemorrhagic cystitis secondary to BK virus infection upon cytology review, and immunostaining confirmed a polyomavirus infection of the urothelium. The patient\u27s symptoms resolved after a modification of his immunosuppressive regimen, and antiviral therapy was ultimately unnecessary. Though symptomatic BK virus infection of the genitourinary tract is common in immunosuppressed transplant patients, its occurrence in a patient undergoing immunomodulation for an autoimmune disease has not been reported yet. This case illustrates the potential for active BK virus infections in atypical patient populations and underscores the importance of rigorous hematuria workup, particularly in patients with multiple risk factors

Maternal and congenital syphilis in rural Haiti Sífilis materna y congénita en zonas rurales de Haití

OBJECTIVES: A study was conducted to assess the prevalence of maternal syphilis and estimate the rate of congenital syphilis in five rural villages surrounding Jeremie, Haiti. METHODS: This research was a retrospective observational study. Data were extracted from the Haitian Health Foundation's public health database and verified through original clinical paper records, death certificates, midwife reports, and discussions with community health workers. Data were analyzed by chi-square analysis, bivariate correlations, and two-tailed t-test for independent samples. RESULTS: Of the 410 women tested for syphilis, 31 (7.6%) were sero-reactive. Average gestation at time of testing was 25 weeks, which correlated with entry into prenatal care at an average of 23 weeks. Women who tested positive during pregnancy were more likely to have had a negative pregnancy outcome than those who did not (chi square = 16.4; P < 0.0001). The estimated rate of congenital syphilis in the region was 767 per 100,000 live births. CONCLUSIONS: Maternal syphilis is prevalent in rural Haiti. This prevalence combined with late entry into prenatal care contributes to adverse pregnancy outcomes and a high estimated rate of congenital syphilis. More research is needed on congenital syphilis and prenatal-care-seeking practices of rural Haitian women in order to understand the impact of maternal syphilis in the region and improve pregnancy outcomes.<br>OBJETIVOS: Evaluar la prevalencia de sífilis materna y estimar la tasa de sífilis congénita en cinco poblaciones rurales cercanas a Jeremie, Haití. MÉTODOS: Estudio observacional retrospectivo a partir de datos extraídos de la base de datos de salud pública de la Fundación Haitiana de Salud y verificada con los registros clínicos originales en papel, los certificados de defunción, los informes de las parteras y discusiones con los trabajadores comunitarios de salud. Los datos se analizaron mediante la prueba de la ji al cuadrado, correlaciones bifactoriales y la prueba de la t de dos colas para muestras independientes. RESULTADOS: De las 410 mujeres sometidas a la prueba de sífilis, 31 (7,6%) resultaron seropositivas. La edad gestacional promedio al momento de la prueba fue de 25 semanas, lo que se correlacionó con la edad gestacional de entrada a la atención prenatal (23 semanas). Las mujeres que resultaron seropositivas durante el embarazo presentaron mayor probabilidad de tener un desenlace negativo de su embarazo que las mujeres que resultaron seronegativas (&#967;2 = 16,4; P < 0,0001). La tasa estimada de sífilis congénita en la zona fue de 767 por 100000 nacidos vivos. CONCLUSIONES: La sífilis materna es frecuente en las zonas rurales de Haití, lo que combinado con la entrada tardía a los servicios de atención prenatal, contribuye a los desenlaces adversos de los embarazos y a la alta tasa estimada de sífilis congénita. Se requieren más estudios sobre la sífilis congénita y los hábitos de búsqueda de atención prenatal de las mujeres de zonas rurales de Haití para comprender el impacto de la sífilis materna en esta parte del país y mejorar el desenlace de los embarazos

The health care relationship (HCR) trust scale: development and psychometric evaluation

A sequential multi-method approach using focus groups, individual interviews, and quantitative instrument development procedures was used to develop and evaluate a scale to measure patient trust in health care providers (HCPs). The resulting 15-item Health Care Relationship (HCR) Trust Scale was tested for internal consistency, test-retest reliability, and construct validity. The Cronbach alphas were .92 (time 1) and .95 (time 2), respectively. Test-retest reliability was .59 (p \u3c .01). The HCR Trust Scale did not correlate with the Marlowe-Crowne Social Desirability Scale (r = .20, p = .07) or the Rapid Estimate of Adult Literacy in Medicine scale (r = -.21, p = .13). Principal component factor analysis with varimax rotation revealed a three-factor solution that explained 69% of the estimated common variance in the HCR trust scale. Cronbach alphas for the 3 factors ranged from .81 to .89. Findings of this study support the use of the HCR Trust Scale for measuring trust in various HCPs by diverse patient populations. More work is needed to test the usefulness of the scale with a greater number of patients and in other chronic illness populations

Electronic monitoring device event modelling on an individual-subject basis using adaptive Poisson regression

An adaptive approach to Poisson regression modelling is presented for analysing event data from electronic devices monitoring medication-taking. The emphasis is on applying this approach to data for individual subjects although it also applies to data for multiple subjects. This approach provides for visualization of adherence patterns as well as for objective comparison of actual device use with prescribed medication-taking. Example analyses are presented using data on openings of electronic pill bottle caps monitoring adherence of subjects with HIV undergoing highly active antiretroviral therapies. The modelling approach consists of partitioning the observation period, computing grouped event counts/rates for intervals in this partition, and modelling these event counts/rates in terms of elapsed time after entry into the study using Poisson regression. These models are based on adaptively selected sets of power transforms of elapsed time determined by rule-based heuristic search through arbitrary sets of parametric models, thereby effectively generating a smooth non-parametric regression fit to the data. Models are compared using k-fold likelihood cross-validation

Use of electronic monitoring devices to measure antiretroviral adherence: practical considerations

The purpose of this paper is to describe electronic monitoring device (EMD) (e.g., MEMS caps) use among HIV-infected adults enrolled in a randomized clinical trial and to make explicit some of the benefits and caveats of using electronic monitoring device technology. This is a descriptive, exploratory study of EMD use among 128 HIV-infected adults treated with at least three antiretroviral agents. Thirty-six percent of the sample admitted that they did not use the EMD consistently. Forty-one percent of the subjects reported taking out more than one dose at a time and 26% reported opening the EMD but not taking the medication. Special subject-related issues accounted for only a small percentage of all reported problems with EMD use (e.g., transient housing, incarceration, substance abuse relapse and drug treatment). Results of this study suggest that EMDs may underestimate antiretroviral adherence among HIV-infected adults. Recommendations for improving EMD data quality are presented

Home visits to improve adherence to highly active antiretroviral therapy: a randomized controlled trial

BACKGROUND: Few rigorously designed studies have documented the efficacy of interventions to improve medication adherence among patients prescribed highly active antiretroviral. Data are needed to justify the use of limited resources for these programs. METHODS: A 2-arm, randomized, controlled trial evaluated the efficacy of a community-based, home-visit intervention to improve medication adherence. Participants were 171 HIV-infected adults prescribed a minimum of 3 antiretroviral agents. The majority had a past or current history of substance abuse. Subjects were randomly assigned to receive home visits for 1 year or usual care. Medication adherence was assessed with Medication Event Monitoring stem caps at 3-month intervals from randomization through 3 months after the conclusion of the intervention. RESULTS: A larger proportion of subjects in the intervention group demonstrated adherence greater than 90% compared with the control group at each time point after baseline. The difference over time was statistically significant (Extended Mantel-Haenszel test: 5.80, P = 0.02). A statistically significant intervention effect on HIV-RNA level or CD4 cell count was not seen, but there was a statistically significant association between greater than 90% adherence and an undetectable HIV-RNA over time (P \u3c 0.03). CONCLUSION: Home visits from a nurse and a community worker were associated with medication adherence greater than 90% among a cohort of socially vulnerable people living with HIV/AIDS in northeastern United States