David J. Hardy

Medication adherence in HIV-infected adults: Effect of patient age, cognitive status, and substance abuse

Objective: To examine the predictors of antiretroviral adherence among HIV-infected adults, with a particular focus on advancing age, neuropsychological dysfunction, and substance abuse. Design: Prospective observational design. Methods: Participants were 148 HIV-infected adults between the ages of 25 and 69 years, all on a self-administered antiretroviral regimen. Medication adherence was tracked over a one-month period using an electronic monitoring device (medication event monitoring system caps). All participants completed a comprehensive battery of neuropsychological tests as well as a structured psychiatric interview. Results: The mean adherence rate for the entire cohort was 80.7%, with older patients (⩾ 50 years) demonstrating significantly better medication adherence than younger patients (87.5 versus 78.3%). Logistic regression analyses found that older patients were three times more likely to be classified as good adherers (defined as ⩾ 95% adherent). Neurocognitive impairment conferred a 2.5 times greater risk of poor adherence. Among the older patients, those who were classified as poor adherers performed significantly worse on neuropsychological testing, particularly on measures of executive function and psychomotor speed. Current drug abuse/dependence, but not current alcohol abuse/dependence, was also associated with sub-optimal medication adherence. Conclusion: Although older age is associated with higher rates of antiretroviral adherence, older participants who were cognitively impaired showed disproportionate difficulty in adequately adhering to their medication regimen. As such, efforts to detect neuropsychological dysfunction, particularly among older patients, and a thorough assessment of substance abuse, appear to be essential for the effective treatment of HIV-infected adults.

Medication adherence among HIV+ adults: Effects of cognitive dysfunction and regimen complexity

Background: Although the use of highly active antiretroviral therapy in the treatment of HIV infection has led to considerable improvement in morbidity and mortality, unless patients are adherent to their drug regimen (i.e., at least 90 to 95% of doses taken), viral replication may ensue and drug-resistant strains of the virus may emerge. Methods: The authors studied the extent to which neuropsychological compromise and medication regimen complexity are predictive of poor adherence in a convenience sample of 137 HIV-infected adults. Medication adherence was tracked through the use of electronic monitoring technology (MEMS caps). Results: Two-way analysis of variance revealed that neurocognitive compromise as well as complex medication regimens were associated with significantly lower adherence rates. Cognitively compromised participants on more complex regimens had the greatest difficulty with adherence. Deficits in executive function, memory, and attention were associated with poor adherence. Logistic regression analysis demonstrated that neuropsychological compromise was associated with a 2.3 times greater risk of adherence failure. Older age (>50 years) was also found to be associated with significantly better adherence. Conclusions: HIV-infected adults with significant neurocognitive compromise are at risk for poor medication adherence, particularly if they have been prescribed a complex dosing regimen. As such, simpler dosing schedules for more cognitively impaired patients might improve adherence.

Treatment of Cytomegalovirus Retinopathy with Ganciclovir

Ganciclovir is an experimental antiviral drug with activity against human cytomegalovirus (CMV). Forty patients with acquired immune deficiency syndrome (AIDS) and CMV retinopathy were treated with ganciclovir on a compassionate protocol basis. Initial treatment doses ranged from 5.0 to 14.0 mg/kg/day for 9 to 26 days. Signs of drug response were a halt to enlargement of lesions, decreased opacification of retinal tissue, and resolution of hemorrhage and vasculitis. Complete response was seen in 88% of patients and incomplete response was seen in 9%. Vision improved or remained stable in 88% of patients. Initial treatment did not eradicate live virus from the eye. To prevent reactivation of disease, 26 patients received low-dose maintenance therapy ranging from 1.5 to 7.5 mg/kg/day, once or twice daily, 3 to 7 days per week. Reactivation of disease developed for unknown reasons in 50% of patients on continuous, uninterrupted maintenance therapy for longer than 3 weeks. Reversible neutropenia, requiring cessation of treatment, developed in 30% of patients on initial treatment and in 38% of patients on maintenance therapy. Rhegmatogenous retinal detachment was a late complication in seven patients. By reducing or delaying visual loss, ganciclovir appears to be useful in the management of CMV retinopathy in patients with AIDS.

Brain and cognitive reserve: Mediator(s) and construct validity, a critique

The concept of “reserve” has traditionally been defined on the basis of a single indicator (e.g., education or intracranial volume) that purports to moderate or buffer the effects of brain damage on different clinical outcomes. While studies have shown modest effects for some indicators, it has left the concept of “reserve” wanting as an explanatory construct. More recently efforts have been made to identify groups of indicators hypothesized to represent a construct for brain or cognitive reserve. These efforts have also proved wanting because of the lack of evidence to justify such a priori groupings of variables into a brain or cognitive reserve construct. This theoretical paper addresses the issue of construct validity (convergent and discriminant) for both brain and cognitive reserve as single or multiple reserve factors. Conceptual models are proposed that are (a) derived from the current extant reserve literature and (b) empirically testable in order to facilitate establishment of construct validity for the commonly used, and perhaps misused, brain and cognitive reserve concepts.

The Neuropsychology of HIV/AIDS in Older Adults

Highly active antiretroviral therapy is allowing increasing numbers of adults to age with HIV. The neuropsychological effects of aging with HIV are reviewed through three types of studies. First, the separate effects of HIV and aging on cognition are examined in studies that compare younger adults with HIV with neurologically normal older adults. Second, studies examine the impact of aging within samples of adults with HIV only. Third, providing the most critical evidence, are studies that assess cognition in younger and older adults with HIV relative to younger and older adults without HIV. In general research findings are inconclusive. Large individual differences among older adults with HIV as well as co-factors (APOE4 and detectable viral load) may account for inconsistent findings in the literature. A subgroup of older adults with HIV may be at greater risk for cognitive impairment, especially in attention functioning.

Variations in Patterns of Highly Active Antiretroviral Therapy (HAART) Adherence

Strict adherence to highly active antiretroviral therapy (HAART) is necessary for successful suppression of HIV replication. A large number of individuals are not adherent, however, and the reasons for non-adherence are varied and complex. We utilized cluster analyses to identify subgroups of adherers in a sample of 222 HIV positive individuals whose HAART use was electronically monitored. Five distinct subgroups were identified, with characteristic variations across the week and over the course of the 4-week study. Additional comparisons of demographic and behavioral variables found the worst adherers to have higher rates of substance use, and that a group with higher rates of cognitive impairment had a consistent drop in adherence during the weekends. In addition, the group with the best adherence had more individuals over the age of 50 years. The results of the current study indicate that distinct subgroups of adherers may exist, and suggest that interventions designed to improve adherence can be designed to accommodate this variability in behavior.

Components of depression in HIV-1 infection : Their differential relationship to neurocognitive performance

Both depression and neurocognitive compromise are commonly observed among persons infected with the Human Immunodeficiency Virus (HIV). To date, the majority of studies have failed to find a consistent relationship between mood and cognition among HIV-seropositive (HIV+) individuals, suggesting that these constructs are independent of one another. However, depression is a multi-dimensional syndrome and its measurement often utilizes multi-factorial instruments containing cognitive, affective, somatic, and motivational components. The degree to which various symptoms or dimensions of depression might be related to neuropsychological performance in HIV-1 infection is not typically explored and was a main objective of the current study. A sample of 247 HIV+ persons completed both a comprehensive neurocognitive battery and the Beck Depression Inventory (BDI) as part of a standard clinical evaluation at a major community hospital. To examine the dimensionality of the BDI, a principal components analysis was conducted which suggested a three-factor solution comprised of factors representing Self-Reproach (SR), Mood-Motivation Disturbance (MM), and Somatic Disturbance (SOM). The relationship between each of these three factors and neurocognitive performance was examined using both regression and analysis of variance techniques. These analyses showed the MM factor, more so than either the SR or SOM factors, to be associated with several aspects of neurocognitive performance, including verbal memory, executive functioning, and motor speed. These findings suggest that certain items on depression rating scales may be more indicative of central nervous system (CNS) involvement than others. The association between disturbance in mood and motivation and neurocognitive compromise may suggest that each are sequelae of disease specific mechanisms. This research was supported in part by grants from the National Institute of Mental Health (RO1MH58552; T32MH19535), the University of California Universitywide AIDS Research Program (F98-LA-125) and the UCLA Academic Senate. We would like to thank Marta Stefaniak for her assistance with manuscript preparation. Portions of this paper were presented at the 28th Annual Meeting of the International Neuropsychological Society in Boston, Massachusetts.

Phase 1 Trial of a Single Dose of Recombinant Human Interleukin—12 in Human Immunodeficiency Virus—Infected Patients with 100–500 CD4 Cells/µL

A phase 1 dose-escalation trial of a single subcutaneous dose of recombinant human (rh) interleukin (IL)-12 was conducted in medically stable human immunodeficiency virus (HIV)-infected patients with 100-500/microL absolute CD4(+) T lymphocytes. Subjects at each dose level were randomly assigned (3:1) to receive rhIL-12 or placebo. Among the 47 subjects enrolled, rhIL-12 was well tolerated at doses of 3-300 ng/kg, but 4 of 5 subjects who received rhIL-12 at 1000 ng/kg had severe adverse events. Dose-related increases in serum interferon-gamma occurred after rhIL-12 administration at doses > or =30 ng/kg. There was no effect of rhIL-12 on plasma HIV RNA or absolute CD4(+) T cell counts. However, dose-related increases in absolute CD8(+) T and NK cells were observed in subjects assigned to rhIL-12 doses of 30-300 ng/kg. Single rhIL-12 doses of 30-300 ng/kg were well tolerated and had biologic activity that could potentially be of benefit in the treatment of HIV disease or its complications.

Reaction time performance in adults with HIV/AIDS

Infection with the Human Immunodeficiency Virus - Type 1 (HIV-1) has been shown to lead to cognitive decline in a substantial proportion of infected adults. The characteristic neuropsychological symptomatology includes memory dysfunction, higher order attentional disturbance, executive dysfunction and, most relevant to this manuscript, cognitive slowing. This paper reviews the extant literature on reaction time (RT) performance in HIV-infected adults with an emphasis on mental chronometry. In addition to discussing studies of simple and choice RT, we also examine the utility of RT paradigms in the assessment of selective attention, covert orienting, sustained attention, divided attention, working memory, and implicit memory. Studies documenting the utility of RT tasks to track treatment response are also introduced. In aggregate, research to date that has employed RT tasks in the evaluation of HIV-infected patients has found that HIV infection leads to a mild degree of cognitive slowing that tends to worsen with increasing disease severity. It needs to be noted, however, that a significant percentage of studies failed to find HIV infection to lead to RT slowing. Results of Brinley plot analyses, a technique that shares commonalities with meta-analysis, reveal that HIV-infected patients diagnosed with AIDS are on an average 22% slower than uninfected controls. This paper also reviews data that has shown that HIV associated cognitive slowing, as indexed by single and dual choice RT, is amenable to pharmacologic intervention using the psychostimulant methylphenidate. Given the demonstrated sensitivity of RT tasks to the neuropsychological effects of HIV infection, it is recommended that RT tasks be included whenever possible in the routine clinical evaluation of HIV-infected patients.

Verbal and spatial working memory performance among HIV-infected adults.

Subtypes of working memory performance were examined in a cohort of 50 HIV-infected adults and 23 uninfected controls using an n-back paradigm (2-back) in which alphabetic stimuli were quasi-randomly presented to a quadrant of a computer monitor. In the verbal working memory condition, participants determined whether each successive letter matched the letter that appeared two previously in the series, regardless of spatial location. In the spatial working memory condition, participants determined whether each letter matched the spatial location of the letter that had appeared two previously, regardless of letter identity. The dependent variable was percent accuracy in each condition. Results of mixed model ANOVA revealed that the HIV-infected participants performed significantly worse than controls on both the verbal and spatial working memory tasks. A significant main effect for working memory condition was also present with both participant groups performing better on the spatial working memory task. These results, the first study of HIV-infected adults to directly compare verbal versus spatial working memory performance using the identical test stimuli across task conditions, suggests that HIV infection is associated with a decrement in working memory efficiency that is equally apparent for both verbal and spatial processing. These findings implicate central executive dysfunction as a likely substrate and provide the basis for hypothesizing that decline in working memory may contribute to other HIV-associated neuropsychological deficits.