Christopher F. Ake

HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.

Objectives: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). Methods: A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Results: Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm3 (30% vs 47% in remaining subgroups). Conclusions: The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

Long-term survival and serious cardiovascular events in HIV-infected patients treated with highly active antiretroviral therapy

There is continuing interest in the longer term effects of highly active antiretroviral therapy (HAART) on the risk of cardiopulmonary events. We assessed this using updated administrative data from an open retrospective cohort of HIV-infected persons receiving care from the US Veterans Affairs (VA). Information on 41,213 HIV-infected patients receiving VA care between January 1993 and December 2003 was included. Patients were followed for an average of 4 years or 168,213 person-years of follow-up. The death rate fell from 20.9 deaths per 100 patient-years of observation in 1995 to 5.2 deaths per 100 patient-years in 2003. In patient-level analysis, adjusted hazard ratios for death dropped precipitously for all races to a low of 0.18 (95% confidence interval: 0.15 to 0.23) at 72 months of exposure to HAART. Hazards for serious cardiovascular events remained near 1.0 for exposure to HAART, and hazards for serious cardiovascular events, stroke, or death were only slightly higher than for death alone. No selection effects or secular trends were found. The benefits of HAART continued to increase in the 8 years after introduction and with 6 years of individual use. The risk of serious cardiovascular events should be factored into individual patient management but does not pose an important public health risk.PURPOSE A recent increase in Acanthamoeba keratitis (AK) cases has been associated with Complete MoisturePlus, although many cases used other solutions. Complete MoisturePlus contains taurine and hydroxypropyl methylcellulose, unlike other multipurpose solutions (MPSs). The purpose of this study is to (1) determine contact lens solution efficacy against recent clinical and tap water Acanthamoeba isolates and (2) determine whether taurine inclusion increases Acanthamoeba survival against contact lens solutions. METHODS Acanthamoeba T4 trophozoites from recent AK clinical and tap water isolates were placed on multiple concentrations of taurine-saline agar for 72 hours with Enterobacter aerogenes as prey. Amoebae were exposed for 6 and 24 hours to hydrogen peroxide solutions and MPSs (ReNu Multiplus, Complete MoisturePlus, AMO Trade Name, Opti-free Express, Clear Care, and UltraCare) and tested for survival. Plates were examined over the following week for growth. RESULTS Strain type and solution affected survival. MPSs were ineffective, with 100% survival of all strains at 6-hour exposure. Hydrogen peroxide systems were more effective, with survival of 3/5 strains (Clear Care) and 1/5 strains (UltraCare) at 6 hours. The Chicago-area tap water strain was most resistant. Among hydrogen peroxide systems, no statistically significant difference in Acanthamoeba survival existed with taurine inclusion. CONCLUSIONS Recent clinical and tap water Acanthamoeba strains, representing proven human pathogens and/or household strains, were highly virulent against contact lens solutions. The Chicago-area tap water strain was most resilient, a concern if tap water is contributing to the AK increase. Results further differentiated resistance among T4 strains, highlighting the importance of multiple strain testing.

Neurobehavioral effects of human immunodeficiency virus infection among former plasma donors in rural China.

The human immunodeficiency virus (HIV) epidemic in China has expanded rapidly in recent years, but little is known about the prevalence and features of HIV-associated neurocognitive disorders (HANDs) in this part of the world. We administered a comprehensive Western neuropsychological (NP) test battery to 203 HIV+ and 198 HIV − former plasma donors in the rural area of Anhui province. They found that 26% of the HIV − samples, and 46% of the HIV+ samples, were infected with hepatitis C virus (HCV), which can also have central nervous system (CNS) effects. To classify NP impairment, we developed demographically corrected test norms based upon individuals free of both infections (N=141). Using a global summary score, NP impairment was found in 34.2% of the HIV-monoinfected group and 39.7% of the coinfected group, as compared to 12.7% of the uninfected controls (P <.001). HIV+ participants with acquired immunodeficiency syndrome (AIDS) were more likely to be impaired (43%) than non-AIDS individuals (29%; P <.05). Lastly, when all infection groups were combined, participants with NP impairment reported more cognitive complaints (P <.01) and increased dependence in everyday functioning (P=.01). In sum, NP impairment in this large rural Chinese sample was associated with both HIV and HCV infections, and the impairment’s prevalence, severity, and pattern were similar to those reported by Western studies. Clinical significance of NP impairment in this population is suggested by the participants’ reports of reduced everyday functioning. These findings indicate that HAND is likely to be an important feature of HIV infection in developing countries, underscoring the need for international efforts to develop CNS-relevant treatments.

Clean Indoor Air: Advances in California, 1990–1999

OBJECTIVES This study assessed progress in achieving clean indoor air in California. METHODS Data were from large, cross-sectional population-based surveys (1990-1999). RESULTS Indoor workers reporting smoke-free workplaces increased from 35.0% (95% confidence interval [CI] = 33.7, 36.3) in 1990 to 93.4% (95% CI = 92.6, 94.2) in 1999. Exposure of nonsmoking indoor workers to secondhand tobacco smoke decreased from 29.0% (95% CI = 27.2, 30.8) to 15.6% (95% CI = 14.1, 17.1). Adults with smoke-free homes increased from 37.6 % (95% CI = 35.1, 40.1) in 1992 to 73.7% (95% CI = 73.2, 74.2) in 1999; nearly half of smokers in 1999 had smoke-free homes. In 1999, 82.2% (95% CI = 81.5, 82.9) of children and adolescents (0-17 years) had smoke-free homes, up from 38.0% (95% CI = 35.1, 40.9) in 1992. CONCLUSIONS Californias advances highlight an important opportunity for tobacco control.

Human Immunodeficiency Virus Protease Inhibitors and Risk for Peripheral Neuropathy

Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long‐term use in highly active ARV therapy.

Negative mood and sexual behavior among non-monogamous men who have sex with men in the context of methamphetamine and HIV

BACKGROUND Research comparing the independent and combined contextual effects of methamphetamine dependence (METH) and HIV-infection (HIV) on mood and sexual behavior among men who have sex with men (MSM) has been sparse and inconsistent. This study examined the contextual influence of METH, HIV-infection and their combination on mood states and sexual behavior. METHODS 175 non-monogamous MSM concordant or discordant for METH and HIV were included. Multivariate analysis was conducted to examine mood and sexual behavior differences between groups, as well as to elucidate the relationship between mood and sexual risk behavior and explore the potential moderator (i.e. contextual) effects of METH and/or HIV on this relationship. RESULTS METH+/HIV+ participants reported condom use less than 25% of the time whereas METH-/HIV+ participants reported condom use 51-75% of the time. METH+ and HIV+ status were associated with higher depression and confusion scores. Univariate regressions revealed negative relationships between mood states (depression, tension, anger, fatigue and confusion) and condom use. Neither METH nor HIV status moderated the relationships between negative mood and condom use. LIMITATIONS Results are derived from cross-sectional data, sample sizes for each of the four groups were relatively small, and condom use could not be linked to specific sexual practices and/or partner types. CONCLUSION METH dependence, HIV seropositivity, and negative moods are associated with reduced condom use among non-monogamous MSM. Independent effects of METH dependence and negative mood on condom use suggest that sexual risk reduction interventions for MSM should incorporate multi-faceted approaches, including substance abuse and mental health treatment.

Neurobehavioral effects of HIV-1 infection in China and the United States: A pilot study

The HIV epidemic in China has been increasing exponentially, yet there have been no studies of the neurobehavioral effects of HIV infection in that country. Most neuroAIDS research has been conducted in Western countries using Western neuropsychological (NP) methods, and it is unclear whether these testing methods are appropriate for use in China. Twenty-eight HIV seropositive (HIV+) and twenty-three HIV seronegative (HIV-) individuals with comparable gender, age, and education distributions were recruited in Beijing and the rural Anhui province in China. Thirty-nine HIV+ and thirty-one HIV- individuals were selected from a larger U.S. cohort recruited at the HIV Neurobehavioral Research Center, in San Diego, to be matched to the Chinese sample for age, disease status, and treatment variables. The NP test battery used with the U.S. and China cohorts included instruments widely used to study HIV infection in the United States. It consisted of 14 individual test measures, each assigned to one of seven ability areas thought to be especially vulnerable to effects of HIV on the brain (i.e., verbal fluency, abstraction/executive function, speed of information processing, working memory, learning, delayed recall, and motor function). To explore the cross-cultural equivalence and validity of the NP measures, we compared our Chinese and U.S. samples on the individual tests, as well as mean scaled scores for the total battery and seven ability domains. On each NP test measure, the mean of the Chinese HIV+ group was worse than that of the HIV- group. A series of 2x2 analyses of variance involving HIV+ and HIV- groups from both countries revealed highly significant HIV effects on the Global and all Domain mean scaled scores. Country effects appeared on two of the individual ability areas, at least partly due to education differences between the two countries. Importantly, the absence of HIV-by-Country interactions suggests that the NP effects of HIV are similar in the two countries. The NP test battery that was chosen and adapted for use in this study of HIV in China appears to have good cross-cultural equivalence, but appropriate Chinese norms will be needed to identify disease-related impairment in individual Chinese people. To inform the development of such norms, a much larger study of demographic effects will be needed, especially considering the wide range of education in that country.

Incidence and nature of cognitive decline over 1 year among HIV-infected former plasma donors in China.

Objective:To quantify and characterize the nature of cognitive change over 1 year in a cohort of HIV-positive former plasma donors in rural China. Design:The present study is an observational cohort study. Methods:One hundred and ninety-two HIV-positive and 101 demographically comparable HIV-negative individuals, all former plasma donors, who lived in a rural part of China, received comprehensive medical and neuropsychological examinations. At study entry, 56% of HIV-positive group was on combination antiretroviral treatment and 60.9% at follow-up. Multiple regression change score approach was used with the HIV-negative sample to develop norms for change that would be then applied to the HIV-positive participants. Follow-up test scores adjusted for the control group practice effect. Results:Fifty-three HIV-positive individuals (27%) developed significant cognitive decline as compared with five (5%) HIV-negative individuals. Cognitive decline was predicted at baseline by AIDS status, lower nadir CD4, and worse processing speed; at follow-up, it was associated with lower current CD4 cell count and failure of viral suppression on combination antiretroviral treatment. Neuropsychological decline also was associated with decreased independence in activities of daily living. Using neuropsychological impairment scores that were corrected for ‘practice’ on repeated testing, we found that among the decliners, 41.5% (N = 22) had incident impairment, whereas 38% (N = 20) declined within the impaired range and another 20.7% (N = 11) declined within the normal range. Conclusion:The present study demonstrates that despite ongoing combination antiretroviral treatment, cognitive decline in HIV-positive people is common over a 1-year follow-up. Regression-based norms for change on western neuropsychological tests can be used to detect disease-related cognitive decline in a developing country.

Alteration of Methamphetamine-induced stereotypic behaviour in transgenic mice expressing HIV-1 envelope protein gp120.

The use of drugs for recreational purposes, in particular Methamphetamine, is associated with an increased risk of infection with human immunodeficiency virus (HIV)-1. HIV-1 infection in turn can lead to HIV-associated neurological disorders (HAND) that range from mild cognitive and motor impairment to HIV-associated dementia (HAD). Interestingly, post mortem brain specimens from HAD patients and transgenic (tg) mice expressing the viral envelope protein gp120 in the central nervous system display similar neuropathological signs. In HIV patients, the use of Methamphetamine appears to aggravate neurocognitive alterations. In the present study, we injected HIV/gp120tg mice and non-transgenic littermate control animals with Methamphetamine dissolved in Saline or Saline vehicle and assessed locomotion and stereotyped behaviour. We found that HIVgp120-transgenic mice differ significantly from non-transgenic controls in certain domains of their behavioural response to Methamphetamine. Thus this experimental model system may be useful to further study the mechanistic interaction of both the viral envelope protein and the psychostimulant drug in behavioural alterations and neurodegenerative disease.

Simulated effect of tobacco tax variation on latino health in California1

BACKGROUND Over one fourth of the California population was Latino in 1999, and by 2015 Latinos are expected to be the single largest ethnic group in California. Patterns of smoking and nicotine dependence among Latino smokers may be quite different from those of smokers in other ethnic groups. In addition, Latino smokers may be more sensitive to cigarette prices. Therefore, the effect of an increase in cigarette excise taxes on Latino smoking prevalence may be quite large, and consequently the impact on Latino health may be proportionately greater than on population health in general. METHODS We simulated changes in Latino smoking, morbidity, mortality, and quality-adjusted life years (QALYs) that would result from a range of actual and proposed cigarette excise-tax increases using a range of cigarette price-elasticity estimates specific to Latino smokers. Monte Carlo simulation was used to generate confidence intervals. RESULTS Assuming a Latino price elasticity of demand for cigarettes of -1.0, reductions in Latino smoking resulting from an additional