Ned Sacktor

HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990–1998

This study examined the temporal trends in the incidence rates of HIV dementia, cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma from January 1990 to December 1998 in the Multicenter AIDS Cohort Study. The incidence rates for HIV dementia, cryptococcal meningitis, and lymphoma decreased following the introduction of highly active antiretroviral therapy (HAART). The proportion of new cases of HIV dementia with a CD4 count in a higher range (i.e., 201 to 350) since 1996 may be increasing.

HIV-associated cognitive impairment before and after the advent of combination therapy

The objective of this study was to describe the occurrence of HIV dementia and neuropsychological testing abnormalities in a new cohort of HIV-seropositive individuals at high risk for HIV dementia and to compare these results to a cohort before the advent of highly active antiretroviral therapy (HAART). HAART has been associated with improvements in cognitive performance in some HIV-infected patients. However, it is uncertain whether HAART has changed the frequency of specific neurocognitive abnormalities. Baseline data from 272 HIV-seropositive subjects in the Dana cohort recruited from January, 1994, to December, 1995, and 251 HIV-seropositive subjects in the Northeastern AIDS Dementia Consortium (NEAD) cohort recruited from April, 1998, to August, 1999, were compared. Participants in both cohorts received nearly identical assessments. After adjusting for differences in age, education, gender, race, and CD4 count between the two cohorts, there were no differences in the occurrence of HIV dementia or abnormalities either 1 SD or 2 SDs below established norms for any of the neuropsychological tests. Even though HAART has reduced the incidence of HIV dementia, HIV-associated cognitive impairment continues to be a major clinical problem among individuals with advanced infection.

Human immunodeficiency virus-associated dementia: An evolving disease

This article reviews the changing epidemiology of HIV-associated dementia, current concepts of the different patterns of dementia under the influence of highly active antiretroviral therapy, and reviews therapeutic aspects.

The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) is effective in suppressing systemic human immunodeficiency virus (HIV) viral load and has decreased mortality rates and the incidence of systemic opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS). Multiple studies now suggest that the incidence rates of HIV-associated neurological disease and central nervous system (CNS) opportunistic infections also are decreasing. Since the introduction of HAART in 1996, the incidence of HIV dementia has decreased by approximately 50%. The mean CD4 cell count for new cases of HIV dementia is increasing, but it remains as a complication of moderate-advanced immunosuppression. The incidence of HIV-associated distal sensory polyneuropathy has decreased, although the incidence of antiretroviral drug-induced toxic neuropathy has increased. However, as patients with AIDS live longer as a result of HAART, the prevalence of peripheral neuropathy in HIV-seropositive patients may be increasing. The incidence rates of CNS opportunistic infections (cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy) and primary CNS lymphoma have decreased since the introduction of HAART. As patients develop increasing resistance mutations to antiretroviral drugs and with subsequent decline in CD4 cell counts, in the near future, the incidence of HIV-associated neurological disease may begin to rise.

Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort.

Background: Antiretroviral therapy has improved survival for HIV-1-infected individuals. The neuroepidemiologic implications of HIV-1 in an aging population are not well known, particularly the prevalence of HIV-associated dementia (HAD). Methods: The authors report a baseline cross-sectional analysis of 202 HIV-1-seropositive individuals enrolled into one of two groups of the Hawaii Aging with HIV Cohort: older (50 or more years old, n = 106) and younger (20 to 39 years old, n = 96). Neuropsychological, neurologic, medical, and laboratory data were obtained at enrollment. Participant cognitive status was classified (research case definitions) using American Academy of Neurology (1991) criteria in a consensus conference of physicians and neuropsychologists. Results: HAD was more frequent in older (25.2%) compared to younger (13.7%) individuals (p = 0.041) corresponding to an OR of 2.13 (95% CI: 1.02 to 4.44) for the older compared to the younger group. After adjusting for education, race, substance dependence, antiretroviral medication status, viral load, CD4 lymphocyte count, and Beck Depression Inventory score, the odds of having HAD among individuals in the older group was 3.26 (1.32 to 8.07) times that of the younger group. Conclusions: Older age is associated with increased HAD in this HIV-1 cohort. Underlying mechanisms are unclear but do not appear related to duration of HIV-1 infection.

Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap.

Human immunodeficiency virus (HIV)‐associated neurocognitive disorders (HANDs) remain among the most common disorders in people infected with HIV, even in an era when potent antiretroviral therapy is widely deployed. This review discusses the clinical features of HANDs and the implications for more effective treatment. With the improved survival of individuals treated with antiretrovirals, comorbid conditions are increasingly salient, including particularly coinfection with hepatitis C and the effects of aging. This review attempts to answer why there appears to be a therapeutic gap between the salutary effects of antiretroviral regimens and normalization of neurological function. A second gap is found in the understanding of the pathophysiology of HANDs. This review addresses this and discusses the animal models that have helped to elucidate these mechanisms. Although triggered by productive HIV infection of brain macrophages, aberrant and sustained immune activation appears to play a major role in inducing HANDs, and may explain the often incomplete neurological response to highly active antiretroviral therapy. Novel therapies aimed at persistent central nervous system inflammation will be needed to close this gap. ANN NEUROL 2010;67:699–714

Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia.

Objective: To evaluate whether baseline levels of plasma and CSF HIV RNA, tumor necrosis factor alpha (TNFα), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-2 (MMP-2), or macrophage colony stimulating factor (M-CSF) are predictors of incident HIV-associated dementia (HIVD) in a cohort with advanced HIV infection. Methods: A total of 203 nondemented subjects with CD4 lymphocyte counts less than 200/μL, or <300/μL but with cognitive impairment, underwent semiannual neurologic, cognitive, functional, and laboratory assessments. HIVD and minor cognitive motor disorder (MCMD) were defined using American Academy of Neurology criteria. The cumulative incidence of HIVD was estimated using Kaplan-Meier curves. Cox proportional hazards regression models were used to examine the associations between biologic variables and time to HIVD, adjusting for age, sex, years of education, duration of HIV infection, type of antiretroviral use, premorbid IQ score, and presence of MCMD. Results: After a median follow-up time of 20.7 months, 74 (36%) subjects reached the HIVD endpoint. The dementia was mild in 70% of cases. The cumulative incidence of HIVD was 20% at 1 year and 33% at 2 years. Highly active antiretroviral therapy (HAART) was used by 73% of subjects at baseline. A plasma HIV RNA level was undetectable in 23% of subjects and a CSF HIV RNA level was undetectable in 48% of subjects. In adjusted analyses, neither plasma nor CSF HIV RNA levels (log10) were associated with time to HIVD; log10 levels of plasma TNFα (HR 3.07, p = 0.03) and CSF MCP-1 (HR = 3.36, p = 0.06) tended to be associated with time to HIVD. Conclusion: The lack of association between baseline plasma and CSF HIV RNA levels and incident dementia suggests highly active antiretroviral therapy may be affecting CNS viral dynamics, leading to lower HIV RNA levels, and therefore weakening the utility of baseline HIV RNA levels as predictors of HIV-associated dementia.

Incidence of and risk factors for HIV-associated distal sensory polyneuropathy

Objective: To assess the incidence of and risk factors for distal sensory polyneuropathy (DSP) in a cohort of HIV-infected subjects. Methods: We followed 272 subjects semiannually for up to 30 months. DSP was diagnosed if subjects had decreased or absent ankle jerks, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. Subjects were further classified at each visit as having asymptomatic DSP (ADSP) (signs only) or symptomatic DSP (SDSP) if, in addition to the neurologic signs, paresthesias or pain was reported. Results: At baseline, 45% of the subjects did not meet criteria for DSP, 20% met criteria for ADSP, and 35% met criteria for SDSP. Dideoxynucleoside therapy was used by 23% of the patients, and this treatment was independent of their neuropathy status. In longitudinal univariate analyses, history of AIDS diagnoses (hazard ratio [HR] = 1.89; p = 0.02) and lower CD4 cell count (HR = 0.69; p = 0.0006) were risk factors for incident DSP (ADSP or SDSP). However, for incident SDSP only, in addition to history of AIDS diagnoses, mood and neurologic (other than DSP) and functional abnormalities were significant risk factors. Functional abnormalities remained a significant risk factor in a multiple regression analysis. The presence of ADSP and the use of dideoxynucleosides at baseline were not significant risk factors for incident SDSP. The Kaplan–Meier estimate of the 1-year incidence of SDSP was 36%. Conclusion: Subjects with moderate-to-severe immunosuppression from HIV infection commonly have SDSP. However, sex, use of dideoxynucleosides, and presence of ADSP were not significant risk factors for SDSP.

Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men

Background: Combination antiretroviral therapy including protease inhibitors (combo+PI) is effective in suppressing systemic viral load in HIV infection, but its impact on HIV-associated cognitive impairment is unclear. Objective: To determine whether psychomotor speed, a sensitive measure of impairment in HIV dementia, improves with combo+PI compared with other antiretroviral treatments. Methods: A total of 411 HIV-seropositive (HIV+) homosexual men (with longitudinal neuropsychological testing) in the Multicenter AIDS Cohort Study and, in a separate analysis, 282 HIV+ homosexual men with psychomotor slowing at baseline were classified by treatment into four groups: antiretroviral naïve (no antiretroviral medication treatment), monotherapy, combination antiretroviral therapy without protease inhibitors (combo-noPI), and combo+PI. We compared longitudinal performance on three tests of psychomotor speed: the Grooved Pegboard (GP) (nondominant and dominant hands), Trail Making Test B, and the Symbol Digit Modalities Test (SDMT). Results: Relative to antiretroviral-naïve and monotherapy participants, on the GP nondominant hand test, combo+PI participants with abnormal baseline neuropsychological testing showed improved performance (difference = +0.63 standard deviation [SD], p = 0.02). For the SDMT, both combo+PI participants (difference = +0.26 SD, p = 0.03) and combo-noPI participants (difference = +0.29 SD, p = 0.01) with abnormal baseline neuropsychological testing improved compared with antiretroviral-naïve and monotherapy groups. Conclusion: Combo+PI and combo-noPI are associated with improved psychomotor speed performance in HIV+ homosexual men with abnormal neuropsychological testing.

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies — treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism — are needed to reverse or improve HAND-related neurological dysfunction.