Interleukin-6 is associated with mortality and neuropsychiatric outcomes in antiretroviral-naïve adults in Rakai, Uganda.

Serum interleukin-6 (IL-6) and D-dimer have been associated with multiple adverse outcomes in HIV-infected (HIV+) individuals, but their association with neuropsychiatric outcomes, including HIV-associated neurocognitive disorder (HAND) and depression, headaches, and peripheral neuropathy have not been investigated. Three hundred ninety-nine HIV+ antiretroviral therapy (ART)-naïve adults in Rakai, Uganda, were enrolled in a longitudinal cohort study and completed a neurological evaluation, neurocognitive assessment, and venous blood draw. Half of the participants had advanced immunosuppression (CD4 count < 200 cells/µL), and half had moderate immunosuppression (CD4 count 350-500 cells/µL). All-cause mortality was determined by verbal autopsy within 2 years. HAND was determined using Frascati criteria, and depression was defined by the Center for Epidemiologic Studies-Depression (CES-D) scale. Neuropathy was defined as the presence of > 1 neuropathy symptom and > 1 neuropathy sign. Headaches were identified by self-report. Serum D-dimer levels were determined using ELISA and IL-6 levels using singleplex assays. Participants were 53% male, mean age 35 + 8 years, and mean education 5 + 3 years. Participants with advanced immunosuppression had significantly higher levels of IL-6 (p < 0.001) and a trend toward higher D-dimer levels (p = 0.06). IL-6 was higher among participants with HAND (p = 0.01), with depression (p = 0.03) and among those who died within 2 years (p = 0.001) but not those with neuropathy or headaches. D-dimer did not vary significantly by any outcome. Systemic inflammation as measured by serum IL-6 is associated with an increased risk of advanced immunosuppression, all-cause mortality, HAND, and depression but not neuropathy or headaches among ART-naïve HIV+ adults in rural Uganda.

Diagnostic and prognostic biomarkers for HAND.

In 2007, the nosology for HIV-1-associated neurocognitive disorders (HAND) was updated to a primarily neurocognitive disorder. However, currently available diagnostic tools lack the sensitivity and specificity needed for an accurate diagnosis for HAND. Scientists and clinicians, therefore, have been on a quest for an innovative biomarker to diagnose (i.e., diagnostic biomarker) and/or predict (i.e., prognostic biomarker) the progression of HAND in the post-combination antiretroviral therapy (cART) era. The present review examined the utility and challenges of four proposed biomarkers, including neurofilament light (NFL) chain concentration, amyloid (i.e., sAPPα, sAPPß, amyloid ß) and tau proteins (i.e., total tau, phosphorylated tau), resting-state functional magnetic resonance imaging (fMRI), and prepulse inhibition (PPI). Although significant genotypic differences have been observed in NFL chain concentration, sAPPα, sAPPß, amyloid ß, total tau, phosphorylated tau, and resting-state fMRI, inconsistencies and/or assessment limitations (e.g., invasive procedures, lack of disease specificity, cost) challenge their utility as a diagnostic and/or prognostic biomarker for milder forms of neurocognitive impairment (NCI) in the post-cART era. However, critical evaluation of the literature supports the utility of PPI as a powerful diagnostic biomarker with high accuracy (i.e., 86.7-97.1%), sensitivity (i.e., 89.3-100%), and specificity (i.e., 79.5-94.1%). Additionally, the inclusion of multiple CSF and/or plasma markers, rather than a single protein, may provide a more sensitive diagnostic biomarker for HAND; however, a pressing need for additional research remains. Most notably, PPI may serve as a prognostic biomarker for milder forms of NCI, evidenced by its ability to predict later NCI in higher-order cognitive domains with regression coefficients (i.e., r) greater than 0.8. Thus, PPI heralds an opportunity for the development of a brief, noninvasive diagnostic and promising prognostic biomarker for milder forms of NCI in the post-cART era.

Safety and diagnostic value of brain biopsy in HIV patients: a case series and meta-analysis of 1209 patients.

Early brain biopsy may be indicated in HIV patients with focal brain lesion. This study aimed to evaluate and compare the safety and diagnostic value of brain biopsy in HIV patients in the pre-highly active antiretroviral therapy (HAART) versus post-HAART era via meta-analysis. Appropriate studies were identified per search criteria. The local database was retrospectively reviewed to select a similar patient cohort. Patient demographics, brain biopsy technique, histopathology and patient outcomes were extracted from each study. Study-specific outcomes were combined per random-effects model. Outcomes were compared between the pre-HAART and post-HAART era. Correlations between outcomes and baseline characteristics were assessed via meta-regression analysis. The proportions of histopathological diagnosis were tabulated and compared between the pre- and post-HAART era. Survival analysis was performed for patients in the post-HAART era. A total of 26 studies (including the local database) with 1209 patients were included in this meta-analysis. The most common indications for brain biopsy were diagnosis unlikely to be toxoplasmosis (n=8, 42.1%), focal brain lesion (n=5, 26.3%) or both (n=3, 15.8%). The weighted proportions for diagnostic success were 92% (95% CI 90.0% to 93.8%), change in management 57.7% (45.9% to 69.1%) and clinical improvement 36.6% (26.3% to 47.5%). Morbidity and mortality were 5.7% (3.6% to 8.3%) and 0.9% (0.3% to 1.9%), respectively. Diagnostic success rate was significantly higher in the post-HAART than the pre-HAART era (97.5% vs 91.9%, p=0.047). The odds ratio (OR) for diagnostic success in patients with contrast-enhanced lesions was 2.54 ((1.25 to 5.15), p<0.01). The median survival for HIV patients who underwent biopsy in the post-HAART era was 225 days (90-2446). Brain biopsy in HIV patients is safe with high diagnostic yield. Early brain biopsy should be considered in patients without classic presentation of toxoplasmosis encephalitis.

[Treatment of neuro-AIDS on a neurological intensive care unit: epidemiology and predictors of outcome]. / Behandlung von Neuro-Aids auf der neurologischen Intensivstation : Epidemiologie, Outcome und Prädiktoren des Verlaufs.

BACKGROUND: Investigations concerning the outcome for patients suffering from neuro-AIDS treated on a neurological intensive care unit and specific predictors indicating "dead" were analyzed. MATERIAL AND METHODS: A total of 56 patients with a mean age of 39 ± 0.7 years, a mean CD4+ cell count of 130 ± 166 CD4+ cells/µl and viral load of 146,520 ± 198,059 copies/ml were treated on a neurological intensive care unit due to different forms of neuro-AIDS. RESULTS: Of the patients, 34% were immigrants of whom 74% came from sub-Saharan regions. In 57% of the patients the diagnosis of HIV infection was made during therapy on the neurological intensive care unit. The median for the time between diagnosis of HIV infection and the treatment on the neurological intensive care unit was 8 days for immigrants and 10 years for residents. The most common manifestations of neuro-AIDS were cerebral toxoplasmosis, cryptococcosis and progressive multifocal leukoencephalopathy (PML). Fifty per cent of the patients (n=28) died during treatment on the neurological intensive care unit. Negative predictors for the outcome "dead" were (a) artificial ventilation, (b) antiretroviral naïve immigrant, (c) primary cerebral lymphoma and (d) missing antiretroviral therapy as a result of admission to the intensive care unit. DISCUSSION: The rate of death during treatment of neuro-AIDS on a neurological intensive care unit is much higher than during treatment of internal medicine problems of HIV infection. Antiretroviral naïve immigrants show a much higher rate of death compared to residents in Germany. A lot of research and effort is necessary to improve the availability of the Highly Active Anti-Retroviral Therapy (HAART) worldwide in order to improve the outcome especially for immigrants with neuro-AIDS treated on a neurological intensive care unit.

Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score.

OBJECTIVE: We examined if the CNS Penetration-Effectiveness (CPE) score of antiretroviral drugs was associated with survival after a diagnosis of HIV-related encephalopathy, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, or cryptococcal meningitis. METHODS: Using data from the FHDH-ANRS CO4, we compared the survival of 9,932 HIV-infected patients diagnosed with a first neurologic AIDS-defining event in the pre-combination antiretroviral therapy (cART) (1992-1995), early cART (1996-1998), or late cART (1999-2004) periods. Follow-up was subdivided (CPE < 1.5 and CPE ≥ 1.5), and relative rates (RR) of death were estimated using multivariable Poisson regression models. RESULTS: In the pre-cART and early cART periods, regimens with CPE ≥ 1.5 were associated with lower mortality after HIV-related encephalopathy (RR 0.64; 95% confidence interval [CI] 0.47-0.86 and RR 0.45; 95% CI 0.35-0.58) and after PML (RR 0.79; 95% CI 0.55-1.12 and RR 0.45; 95% CI 0.31-0.65), compared to regimens with CPE < 1.5, while in the late cART period there was no association between the CPE score and the mortality. A higher CPE score was also associated with a lower mortality in all periods after cerebral toxoplasmosis (RR 0.68, 95% CI 0.56-0.84) or cryptococcal meningitis (RR 0.50, 95% CI 0.34-0.74). Whatever the neurologic event, these associations were not maintained after adjustment on updated plasma HIV-RNA (missing, <500, ≥500 copies/mL) with RR ranging from 0.82 (95% CI 0.36-1.91) to 1.02 (0.69-1.52). CONCLUSION: At the beginning of the cART era, the CPE score was of importance for survival after severe neurologic event, while in the late cART period, the additional effect of CPE score vanished with more powerful antiretroviral regimens associated with plasma viral load control.

HIV DNA in circulating monocytes as a mechanism to dementia and other HIV complications.

It is broadly accepted that HIV DNA in lymphoid and myeloid cells persists despite combination antiretroviral therapy. Recognized as the Achilles heel to HIV eradication, the role of these peripheral reservoirs in HIV morbidity is less well developed. The burden of HIV DNA in peripheral mononuclear cells is linked to HIV disease outcomes such as time to AIDS diagnosis, survival, and CD4 T-lymphocyte counts. Monocytes are a minor HIV DNA reservoir, and the burden of HIV DNA in these cells appears to be linked to dementia, suggesting that residual infection in this subset is linked to tissue-related HIV complications. Since monocytes are likely involved in trafficking virus to the brain, there is a strong mechanistic link underlying this discovery. Herein, we summarize our current understanding of monocyte HIV DNA and central nervous system dysfunction in humans. We present a model to understand these relationships and suggest possible treatment approaches to be tested.

Cidofovir in combination with HAART and survival in AIDS-associated progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy is a demyelinating disease with a high mortality caused by the JC virus and occurs in about 5% of HIV-infected patients. Highly active anti-retroviral therapy (HAART) has a proven efficacy in prolonging the survival of patients with AIDS-associated PML, but there are differing opinions about adding cidofovir to the treatment of PML. To investigate the benefit of HAART combined with cidofovir, we retrospectively analysed the survival of 33 patients with AIDS-associated PML proven by PCR in CSF, biopsy or at autopsy. Additionally, we also analysed 37 patients with probable PML. Seventeen (51.5%) of the patients with confirmed PML were treated with HAART and 14 (42.4%) with cidofovir in any combination. Of these patients, 13 (39.4%) were treated with HAART and cidofovir in combination, four (12.1%) patients received only HAART without cidofovir and one (3%) patient received only cidofovir without HAART. Fifteen patients did not receive HAART or cidofovir. The cumulative survival was significantly longer in patients with HAART than in patients without HAART (p = 0.006), independent whether cidofovir was given or not. In comparison with single therapy with HAART, the combination of HAART and cidofovir showed no significant increase in survival (p = 0.435). Therefore, a benefit for cidofovir in addition to HAART in the treatment of PML in HIV-infected patients could not be proven.

Neurocognitive impairment and survival in a cohort of HIV-infected patients treated with HAART.

Before the introduction of HAART, HIV-associated neurocognitive impairment (NCI) was recognized as an independent risk factor for death. Since 1996, we conducted a prospective study to assess whether NCI still represents a negative prognostic factor for mortality. Patients were administered measures of neurocognitive function (a battery of 17 neuropsychological tests), clinical and neurological evaluation, laboratory testing, and brain imaging studies. Among the 412 enrolled patients, 224 (54.4%) were neurocognitively impaired and 188 (45.6%) were neurocognitively unimpaired. A durable virological suppression under highly active antiretroviral therapy (HAART) was achieved by 63.3% of unimpaired patients and by 49.6% of impaired patients (p = 0.007). Overall, 47 deaths were recorded, 38 among impaired and 9 among unimpaired patients. At 84 months, the estimated survival proportions in impaired and unimpaired patients were 68.5% and 84.9%, respectively (p < 0.001). At univariate analysis the virological response to HAART was the variable most strongly associated with survival, since patients with virological failure had a nearly 10-fold increased risk of death than those with durable virological suppression (HR = 9.9, 95% CI: 3.9-25.0). After stratification for virological response to HAART, an increased risk of death for neurocognitively impaired patients was seen only among the 182 patients with virological failure (HR: 2.9, 95% CI: 1.2-7.1), while the survival probability of the 230 patients with durable virological suppression was not affected by neurocognitive impairment (p = 0.89). Our results highlight the clinical relevance of HIV-related central nervous system (CNS) involvement in the HAART era, and raise concerns regarding the clinical relevance of CNS involvement as potent antiretroviral therapies become less effective.

Neurological manifestations of HIV infection in Kwazulu-Natal South Africa.

South Africa has one of the fastest growing HIV epidemics in the world and KwaZulu-Natal, one of its nine provinces, is the epicentre of the epidemic. Of the estimated 5.3 million people infected with HIV in South Africa, 1.2 million reside in KwaZulu-Natal. Transmission of HIV is almost exclusively heterosexual, intravenous drug misuse does not occur and the patients attending state hospitals are antiretroviral drug naive. The neurological complications of HIV infection include bacterial and fungal meningitis, intracranial mass lesions, acute disseminated encephalomyelitis, a variety of spinal cord disorders, and peripheral nerve dysfunction. Tuberculous meningitis, especially that due to multidrug resistant organisms has a high mortality rate. Toxoplasmosis is the most frequent cause of intracranial mass lesions. These cases are successfully treated with cotrimoxazole alone. Multiple bacterial abscesses and tuberculomata are other important causes whilst primary central nervous system lymphoma is rare. The spinal cord disorders include co-infection with HTLV-I, tuberculosis and syphilis. Intramedullary tuberculomata, often multiple, and spinal epidural tuberculous abscess without bony disease are seen more commonly than in the pre HIV era. Peripheral nerve dysfunction include Gillian Barre Syndrome, chronic inflammatory demyelinating polyneuropathy and mononeuritis multiplex. Until the antiretroviral therapy roll out programme is well established the above HIV related neurological complications will continue to be seen for several years.

HIV-encephalopathy as initial manifestation of acquired immunodeficiency syndrome in Yucatán State, Mexico.

BACKGROUND: The frequency of neurologic manifestations of the central nervous system (CNS) as a defining disease of acquired immunodeficiency syndrome (AIDS) (neurologic manifestation defining disease [NMDD-AIDS]) varies according to geographic region. The aim of this study was to determine its prevalence among patients with AIDS diagnosed in the state of Yucatán, Mexico. METHODS: We carried out a retrospective study in which AIDS cases reported at the Health Department in the state of Yucatán, Mexico from January 1983 to July 2001 were analyzed. Frequency of NMDD-AIDS and other pathologies were obtained. Frequency of other pathologies between patients with NMDD-AIDS and those without NMDD-AIDS was compared using chi2 and/or Fisher exact test. RESULTS: A total of 1,175 subjects (1,054 [90%] men and 121 [10%] women) were included in the study. In 186 (16%), NMDD-AIDS were observed. The most common NMDD-AIDS was HIV-encephalopathy in 101 (54%) patients, CNS toxoplasmosis in 65 (35%), meningeal cryptococosis in 16 (8.6%), primary lymphoma of the brain in two (1%), and one (0.5%) case of progressive multifocal leukoencephalopathy. CD4 lymphocytes were statistically different between patients with NMDD-AIDS (n=47) and without (n=312) (mean: 65/microL (33-500) vs. 189/microL (2-989), p<0.005). Higher frequency of oropharyngeal candidiasis, pulmonary tuberculosis, herpetic stomatitis, and mortality was observed in patients with initial neurologic disease. CONCLUSIONS: Frequency of NMDD-AIDS was similar to some reports from the U.S. but lower than others from Mexico. HIV-encephalopathy was the most frequent manifestation. NMDD-AIDS were associated with advanced stage of immunodeficiency and influenced morbidity and mortality associated with AIDS.

HIV-related brain impairment from palliative care to rehabilitation.

Brain impairment is a distressing manifestation of human immunodeficiency virus (HIV) disease characterized by progressive cognitive impairment leading eventually to dementia and death. Patients with advanced brain impairment are clinically difficult to manage and usually require residential care. In 1997, a brain impairment unit opened at the Mildmay Hospital UK in London to meet the needs of this patient group. It began as a nurse-led unit, has adopted an interdisciplinary approach to care and aims to maximize the quality of life until death. In a study of patients admitted during its first year, it emerged that while the condition of many patients declined resulting in death, some patients improved sufficiently with rehabilitation and ongoing medical treatment to return to independent living. The possible reasons for this are discussed in this article. Study findings have not only affected the approach to care but have also highlighted some unexpected problems; the importance of adopting an interdisciplinary approach in caring for the group of patients becomes evident.

Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team.

BACKGROUND AND PURPOSE: While MR findings in progressive multifocal leukoencephalopathy (PML) have been described previously, usually in retrospective studies with limited sample size, what has not been well addressed is whether any are predictive of longer survival. Our participation in a large prospective clinical trial of AIDS patients with biopsy-proved PML and MR correlation allowed us to test our hypothesis that certain MR features could be found favorable to patient survival. METHODS: The patient cohort derived from a randomized multicenter clinical trial of cytosine arabinoside for PML. Pretreatment T1- and T2-weighted noncontrast images (n = 48) and T1-weighted contrast-enhanced images (n = 45) of 48 HIV-positive patients with a PML tissue diagnosis as well as the follow-up images in 15 patients were reviewed to determine signal abnormalities, lesion location and size, and the presence or absence of mass effect, contrast enhancement, and atrophy, and to ascertain the frequency of these findings. A statistical analysis was performed to determine if any MR abnormalities, either at baseline or at follow-up, were predictive of patient survival. RESULTS: No MR abnormalities either on univariate or multivariate analysis significantly correlated with patient survival, with the exception of mass effect, which was significantly associated with shorter survival. The mass effect, however, always minimal, was infrequent (five of 48). More severe degrees of cortical atrophy and ventricular dilatation, lesion location and size, and other MR variables were not predictive of outcome. CONCLUSION: Except for mass effect, we found no MR findings predictive of the risk of death in patients with PML. The mass effect, however, was so infrequent and minimal that it was not a useful MR prognostic sign.

HIV-associated primary CNS lymorbidity and utility of brain biopsy.

INTRODUCTION: Human immunodeficiency virus (HIV) infection is associated with several central nervous system (CNS) infections and neoplasms. These opportunistic processes generally occur with advanced immunosuppression, but if an accurate diagnosis is made, effective treatment can frequently be initiated. METHODS: In an attempt to assess the safety, diagnostic yield, and utility of stereotactic brain biopsy in the clinical management of suspected HIV-associated primary CNS lymphoma, we retrospectively studied the performance of biopsy in HIV-seropositive patients presenting with focal intracranial lesions. This analysis included 435 patients undergoing brain biopsy, identified through a local case series (n=47) combined with all published cases (n=388). The years of analysis for this study were 1984 and 1997. We also assessed the survival of HIV-associated intracranial mass lesions and of PCNSL patients treated at JHU. RESULTS: Definitive histopathological diagnoses were established in eighty-eight percent of biopsied cases: primary CNS lymphoma (PCNSL) (30%), CNS toxoplasmosis (CNS TOXO) (16%), progressive multifocal leukoencephalopathy (PML) (25%), and other specific diagnoses (17%). Post-biopsy morbidity within thirty days was 8.4% and mortality was 2.9%. PCNSL was the most common diagnosis among cases biopsied after failure of anti-toxoplasmosis therapy, 134/205 (65%). In the local case series, biopsy-related morbidity was associated with poor functional status, decreased platelet count, and number of lesions at presentation. The median survival of irradiated PCNSL cases was 29 days longer than untreated cases (median survival 50 days versus 21 days, respectively, Chi-square=6.73, P<0.01). DISCUSSION: Stereotactic brain biopsy had a high diagnostic yield for HIV-associated focal intracranial lesions, however, the biopsy complication rate in this patient population was relatively high. PCNSL was diagnosed in the majority of patients failing anti-toxoplasmosis therapy. Survival after irradiation for PCNSL remains very poor.

Brain HIV burden and length of survival after AIDS diagnosis.

Patients with AIDS in the late stages of disease can develop dementia. Previous studies have suggested HIV encephalitis is the pathological substrate of HIV-associated dementia. We hypothesized that patients who survive longer after the initial diagnosis of AIDS would have a higher brain HIV burden and consequently manifest dementia. We examined the relationship between length of survival after AIDS diagnosis and the presence of HIV encephalitis or HIV-associated dementia. We studied retrospectively the following parameters in 74 consecutive AIDS autopsies: length of survival after AIDS diagnosis, clinical diagnosis of dementia, and neuropathologic findings (including HIV burden assessment). Multinucleated giant cells (MNGC) were identified in 20% of the brains studied. HIV gp41 was detected by immunocytochemistry in 54%, approximately half of which had abundant HIV burden. Brains from all 4 patients who were clinically diagnosed with dementia and had no opportunistic neuropathologic changes contained MNGC and abundant HIV burden. Survival after AIDS diagnosis was significantly longer in patients with MNGC (p = 0.03) or abundant HIV burden (p = 0.02). A trend toward longer survival after AIDS diagnosis was apparent in patients with dementia, but did not reach statistical significance. These findings suggest that prolonged survival with immunosuppression may be a prerequisite for the development of HIV encephalitis.

Impact of opportunistic disease on survival in patients with HIV infection.

OBJECTIVE: To assess the impact of opportunistic diseases on survival in patients with HIV disease. METHODS: A cohort of 2081 patients followed for a mean of 30 months was studied. Time-dependent Cox proportional hazards analyses were performed using incident opportunistic diseases and CD4 cell counts as independent variables. RESULTS: During follow-up, 730 (35%) patients died. The occurrence of Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV) disease, Mycobacterium avium complex (MAC) disease, Candida esophagitis, Kaposi's sarcoma, lymphoma, progressive multifocal leukoencephalopathy (PML), dementia, wasting, toxoplasmosis, and cryptosporidiosis were all significantly associated with death, independently of CD4 cell count (all P<0.001 for opportunistic diseases controlling for CD4 cell count). The magnitude of increased risk was greatest for lymphoma [relative hazard (RH), 7.2], PML (RH, 3.9), MAC (RH, 3.0) and CMV (RH, 2.2). Cryptococcosis (RH, 0.94) and herpes zoster (RH, 0.85) were not associated with death. In a multivariate Cox proportional hazards analysis, MAC [RH, 2.56; 95% confidence interval (CI), 2.1-3.1], CMV (RH, 1.63; 95% CI, 1.3-2.1), toxoplasmosis (RH, 1.85; 95% CI, 1.3-2.6), PCP (RH, 1.29; 95% CI, 1.1-1.5), and CD4 cell count were significantly associated with death. Patients who had opportunistic diseases had significantly greatly monthly declines in CD4 counts (-11 x 10(6)/l per month) than those who did not (-6 x 10(6)/l per month; P <0.001). CONCLUSION: Most opportunistic diseases increase the risk of death independently of CD4 cell count. These data support the hypothesis that opportunistic diseases enhance HIV pathogenesis and further underscore the importance of prophylaxis.

Trends in incidence of AIDS illnesses in Australia from 1983 to 1994: the Australian AIDS cohort.

To assess time trends in incidence of AIDS illnesses in Australia, a retrospective cohort of people diagnosed with AIDS from January 1, 1983 to December 31, 1994 in three HIV medicine units in Sydney, Melbourne, and Perth was established. Data on initial and subsequent AIDS illnesses were available for 2580 AIDS cases, or 45% of Australian AIDS notifications over the study period. Males represented 97.2% of the cohort, and HIV exposure category was homosexual contact for 89.9%. Subcohorts were formed by interval of AIDS diagnosis: 1983 through 1987, 1988 through 1990, and 1991 through 1994, with estimation of cumulative risk for each AIDS illness by the Kaplan-Meier method. The cumulative risk declined for Pneumocystis carinii pneumonia (PCP) (p < 0.0001) and for Kaposi's sarcoma (KS) (p < 0.0001); PCP cumulative risk estimates 2 years following AIDS diagnosis were 70% for people diagnosed with AIDS in 1983 through 1987 and 48% in 1991 through 1994, and KS cumulative risk estimates 2 years following AIDS diagnosis were 44% in 1983 through 1987 and 32% in 1991 through 1994. In contrast, cumulative risk increased from 34% to 40% for cytomegalovirus (CMV) disease (p = 0.005), from 47% to 50% for Mycobacterium avium complex (MAC) (p < 0.0001), and from 26% to 33% for esophageal candidiasis (p < 0.0001). Corresponding to this changing spectrum of AIDS illness has been an increase in severity of immunodeficiency at AIDS, with median CD4 cell count declining from 54 cells/mm3 in 1983 through 1987 to 34/mm3 in 1991 through 1994 (p = 0.002).

A comparison of brain biopsy and CSF-PCR in the diagnosis of CNS lesions in AIDS patients.

Twenty patients with AIDS who had intracranial lesions underwent both brain biopsy and cerebrospinal fluid (CSF) examination to compare histological diagnosis with the polymerase chain reaction (CSF-PCR) for the identification of infectious agents. CSF-PCR was performed for herpes simplex virus, varicella zoster virus, cytomegalovirus (CMV), JC virus (JCV), Epstein-Barr virus (EBV), Toxoplasma gondii and Mycobacterium tuberculosis. A definitive diagnosis was obtained by brain biopsy in 14 patients (2 with astrocytoma, 12 with brain infection). CSF-PCR was positive for EBV DNA in 3 of 3 cases of primary cerebral lymphoma, positive for JCV DNA in 6 of 7 biopsy-proven (and one autopsy-proven) cases of progressive multifocal leukoencephalopathy (PML). CSF-PCR was positive for CMV DNA in one biopsy-proven and one autopsy-proven case of CMV encephalitis (the former also had PML) and positive for M. tuberculosis DNA in one case of tuberculous encephalitis. None of the five toxoplasmic encephalitis cases (one definite, four presumptive) were T. gondii DNA positive. There was close correlation between histology and CSF-PCR for CMV encephalitis, PML and PCL. Antitoxoplasma therapy affected the sensitivity of both histological and CSF-PCR methods.

Neuropathological syndromes in the course of full blown acquired immune deficiency syndrome (AIDS) in adults in Poland (1987-1995).

Morphological analysis of the brains from 100 cases of full blown AIDS patients observed in the course of 1987-1995 years was performed. The material comprised 96 males, 3 females and 1 infant, 11 months old. Early material consisted almost exclusively of homo- and bisexuals, while in the last years heterosexual drug addicts prevailed. Gross brain examination revealed focal changes in 25% of cases, most of them being connected either with opportunistic infections or primary proliferating malignancies. Brain atrophy with an evident regional differences was observed macroscopically in 35 cases. Microscopic examination allowed detection of pathological changes in the brains of 87 cases, although in the remaining 13 cases there occurred some slight abnormalities taking the form of non-specific neuronal degeneration and loss, considered as resulting from perimortal cardio-pulmonary insufficiency or bleeding. Specific HIV-related changes in the form of HIV-encephalitis, HIV-encephalopathy or coexistence of both and HIV-leptomeningitis as well as HIV-vasculitis were present in 35 cases. They were accompanied by HIV-associated changes (vacuolar myelopathy, vacuolar leukoencephalopathy and selective poliodystrophy). Very seldom they appeared as independent pathological features and were characterized by very low frequency. Opportunistic infections composed the largest group of 59 cases. Proliferative malignancies occurred altogether in eleven cases, 10 of which were primary and secondary brain lymphomas. One case of Kaposi sarcoma completed the neoplastic series. Sixteen cases revealed various types of brain pathology such as hepatogenic encephalopathy, traumatic cortical scars, central pontine myelinolysis etc. The 59 cases of opportunistic infections consisted of a wide spectrum of viral and bacterial as well as fungal and protozoan infections. Among viral infections cytomegalovirus encephalitis was the most common, way ahead the progressive multifocal leukoencephalopathy. The second in frequency among opportunistic infections was brain toxoplasmosis and some fungal infections such as cryptococcosis and aspergillosis. Bacterial infections were in fact limited to tuberculosis, taking the form of granulomatous leptomeningitis with severe vascular pathology and/or tuberculoma formation. Many pathological processes appearing in a single case was characteristic feature of our collection. There was coexistence of HIV-specific CNS pathology and opportunistic infections, malignant neoplastic growth and other types of pathology. Various opportunistic infections coexisted without HIV-specific changes as well as malignant proliferation with opportunistic infections. Similarities and differences of our series were compared with data characterizing other, earlier collections of NeuroAIDS.

Predicting survival in AIDS: refining the model.

We tested the validity of a previously-published AIDS staging system by examining AIDS-defining diseases (ADDs) and CD4 counts as prognostic factors for survival of the 248 AIDS patients in the Edinburgh City Hospital Cohort, of whom 56% were injecting drug-users (IDUs). Cox regression was used to model the proportionality of risk of death as the CD4 count declined and more ADDs were experienced, and dependence upon post-AIDS treatment. Using the system of Mocroft et al. (Lancet 1995; 346:12-17) to grade severity, our data were well enough modelled, but we suggest: (i) regrading of HIV dementia (RR 3.9, 95% CI 2.5-6.0), mainly attributed to the drug users, to a very severe ADD; (ii) reduction in risk from zidovudine (RR 0.7, 95% CI 0.5-1.0) during AIDS follow-up for patients starting treatment at or after AIDS diagnosis; (iii) improved management of first mild ADDs (from 1987-89 to 1994-95: 40% reduction in IDUs appearing with mild index diseases, and an approximate three-fold reduction in risk associated with a mild ADD). This study supports previous findings on the significance of ADDs and lowest CD4 count in predicting the lifetime of AIDS patients.

Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia.

The pathogenesis of human immunodeficiency virus (HIV)-associated dementia is unclear, and the underlying pathological substrate has been a matter of debate. In a prospectively clinically characterized population of acquired immunodeficiency syndrome (AIDS) patients we investigated the relationship between the clinical syndrome of HIV-associated dementia and the presence and relative quantity of immunocytochemical markers for HIV-1 (gp41 antibody), and for macrophages and microglia (HAM-56 antibody). Sections from the basal ganglia and frontal lobes from the brains of 51 patients were studied, and the data were stratified for severity of dementia (16 nondemented, 12 mildly demented, 23 severely demented), rate of dementia progression, duration of AIDS, use of antiretrovirals, and several other demographic features. We found a highly significant correlation between the degree of macrophage staining and the severity of dementia but only a borderline correlation between the presence and amount of gp41-positive cells and dementia. Several nondemented patients showed abundant gp41 immunoreactivity, and some severely demented showed little to no gp41 immunoreactivity. Other correlations with the immunostaining data, including antiretroviral use, were not significant. We conclude that the presence of macrophages and microglia is a better correlate with HIV-associated dementia than is the presence and amount of HIV-infected cells in the brain. These data support the concept that the pathogenesis of HIV-associated dementia is likely due to indirect effects of HIV infection of the brain, possibly through the actions of macrophages and microglia.