Peter Portegies

Declining incidence of AIDS dementia complex after introduction of zidovudine treatment

OBJECTIVE--To assess the incidence of the AIDS dementia complex and the presence of HIV I p24 antigen in cerebrospinal fluid in relation to zidovudine treatment. DESIGN--Retrospective study of a consecutive series of patients with AIDS from 1982 to 1988. SETTING--An academic centre for AIDS. PATIENTS--196 Patients with AIDS and neurological symptoms examined from 1982 to 1988. INTERVENTIONS--Zidovudine treatment, which was introduced to The Netherlands on 1 May 1987 for patients with severe symptoms of HIV infection (Centers for Disease Control groups IVA, B, C, and D). MAIN OUTCOME MEASURES--Diagnosis of AIDS dementia complex and presence of HIV I p24 antigen in cerebrospinal fluid. RESULTS--The AIDS dementia complex was diagnosed in 40 of the 196 (20%) patients with AIDS. Thirty eight of 107 patients with AIDS (36%) not taking zidovudine developed the AIDS dementia complex compared with two of the 89 (2%) taking the drug (p less than 0.00001). The incidence of the AIDS dementia complex increased to 53% in the first half of 1987, after the introduction of zidovudine in May 1987, decreasing to 10% in the second half of 1987 and to 3% in 1988. Dementia was diagnosed before definition of the AIDS dementia complex (1986) according to DSM-III criteria and there was good agreement between diagnosis before and after 1986. Sixteen of 61 samples of cerebrospinal fluid (26%) from patients with AIDS (10 with the AIDS dementia complex) not taking zidovudine were positive for HIV I p24 antigen, whereas none of 37 cerebrospinal fluid samples from patients with AIDS (two with the AIDS dementia complex) taking zidovudine were positive. CONCLUSIONS--The incidence of AIDS dementia complex in patients with AIDS declined after the introduction of systematic treatment with zidovudine; the AIDS dementia complex might be prevented by inhibiting viral replication in the central nervous system.

Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine

BACKGROUND Treatment and prevention of HIV-1-related central-nervous-system disease may be dependent on penetration of antiretroviral drugs into the central nervous system. Few data are available about cerebrospinal-fluid penetration and concomitant changes of HIV-1-RNA concentrations during treatment with antiretroviral agents. We investigated these effects in HIV-1-infected people. METHODS 28 antiretroviral-naive individuals with CD4 cell counts of 200/microL or more and plasma HIV-1-RNA concentrations of 10,000 or more copies/mL who were free of neurological symptoms were randomly assigned lamivudine plus either stavudine (n = 17) or zidovudine (n = 11). We did lumbar punctures on 28 individuals before and 22 individuals after 12 weeks of treatment to assess HIV-1-RNA and drug concentrations in cerebrospinal fluid. FINDINGS All 28 individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid (median 4.64 log10 copies/mL and 4.20 log10 copies/mL in the lamivudine plus zidovudine and lamivudine plus stavudine groups, respectively). There was no correlation between plasma and cerebrospinal-fluid HIV-1-RNA concentrations (r = 0.18, p = 0.35). After 12 weeks of treatment none of the individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid. The highest drug concentration in the cerebrospinal fluid was for lamivudine followed by stavudine and zidovudine. Concentrations were consistent over time, unlike plasma concentrations. Therefore, we found time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine. INTERPRETATION The two drug combinations were equally effective in the decrease of cerebrospinal fluid HIV-1-RNA concentrations. All drugs penetrated the cerebrospinal fluid. Antiretroviral drugs other than zidovudine might be useful in the prevention of AIDS dementia complex.

HIV-1 infection and cognitive impairment in the cART era: a review.

With the introduction of combination antiretroviral therapy AIDS dementia complex or HIV-associated dementia, as it was termed later, largely disappeared in clinical practice. However, in the past few years, patients, long-term infected and treated, including those with systemically well controlled infection, started to complain about milder memory problems and slowness, difficulties in concentration, planning, and multitasking. Neuropsychological studies have confirmed that cognitive impairment occurs in a substantial (15-50%) proportion of patients. Among HIV-1-infected patients cognitive impairment was and is one of the most feared complications of HIV-1 infection. In addition, neurocognitive impairment may affect adherence to treatment and ultimately result in increased morbidity for systemic disease. So what may be going on in the CNS after so many years of apparently controlled HIV-1 infection is an urgent and important challenge in the field of HIV medicine. In this review we summarize the key currently available data. We describe the clinical neurological and neuropsychological findings, the preferred diagnostic approach with new imaging techniques and cerebrospinal fluid analysis. We try to integrate data on pathogenesis and finally discuss possible therapeutic interventions.

Presentation and course of AIDS dementia complex: 10 years of follow-up in Amsterdam, The Netherlands

ObjectiveTo assess the clinical presentation and course of the AIDS dementia complex (ADC). DesignRetrospective study of a consecutive series of symptomatic HIV-1 -infected patients [Centers for Disease Control and Prevention (CDC) stages IVA, B, C and D] evaluated for neurological symptoms between 1982 and 1992. SettingAn academic referral centre for AIDS. PatientsA total of 536 symptomatic HIV-1-infected patients evaluated for neurological symptoms between 1982 and 1992. InterventionsZidovudine treatment, which was introduced in The Netherlands on 1 May 1987 for patients with severe symptoms of HIV infection (CDC stages IVA, B, C and D). Main outcome measuresDiagnosis of ADC and CD4 cell count, clinical features, neuropsychological abnormalities, computed tomography (CT) and magnetic resonance imaging (MRI) abnormalities, cerebrospinal fluid (CSF) findings and course in patients with ADC. ResultsADC was diagnosed in 40 out of 536 (7.5%) immunosuppressed, neuroiogically symptomatic HIV-1-infected patients in CDC stage IV, and was the AIDS-defining illness in six. The mean CD4 cell count of the 40 patients with ADC was 109 χ 106/1. Neuropsychological abnormalities in 15 out of 17 patients tested were in accordance with subcortical dementia. On CT scan of the brain, 70% showed no or only mild cortical atrophy. MRI was more sensitive than CT scan for detecting white matter abnormalities (73 versus 35%; P = 0.02). CSF examination showed mononuclear pleocytosis in 25%, protein level increase in 55%, and HIV-1 p24 core protein in 38% (13 out of 34). The mean survival was 6.7 months in the 40 ADC patients, but 4 months in 20 patients who had never used zidovudine, compared with 14.8 months in 10 patients who started zidovudine after they were classified as having ADC (P < 0.001). Three of these 10 patients improved remarkably, and two slightly, after starting zidovudine. ADC developed after discontinuation of zidovudine in nine patients. Only one patient developed ADC while receiving 600 mg zidovudine. ConclusionsMRI is more sensitive than CT for detecting white matter abnormalities. To date, there is no specific or sensitive CSF marker for ADC. Zidovudine may improve symptoms and prolong survival in patients with ADC, which rarely developed with continued zidovudine use in our study.

Assessment, Diagnosis, and Treatment of HIV-Associated Neurocognitive Disorder: A Consensus Report of the Mind Exchange Program

Many practical clinical questions regarding the management of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain unanswered. We sought to identify and develop practical answers to key clinical questions in HAND management. Sixty-six specialists from 30 countries provided input into the program, which was overseen by a steering committee. Fourteen questions were rated as being of greatest clinical importance. Answers were drafted by an expert group based on a comprehensive literature review. Sixty-three experts convened to determine consensus and level of evidence for the answers. Consensus was reached on all answers. For instance, good practice suggests that all HIV patients should be screened for HAND early in disease using standardized tools. Follow-up frequency depends on whether HAND is already present or whether clinical data suggest risk for developing HAND. Worsening neurocognitive impairment may trigger consideration of antiretroviral modification when other causes have been excluded. The Mind Exchange program provides practical guidance in the diagnosis, monitoring, and treatment of HAND.

Itraconazole compared with amphotericin B plus flucytosine in Aids patients with cryptococcal meningitis

ObjectiveWe conducted a comparison of itraconazole versus amphotericin B plus flucytosine in the initial treatment of cryptococcal meningitis in patients with AIDS and established the efficacy of itraconazole as maintenance treatment. DesignThe trial was a prospective, randomized, and non-blinded study.Setting: The study was performed at an academic centre for AIDS, Amsterdam, The Netherlands. Patients, participantsTwenty-eight HIV-1-seropositive men with a presumptive diagnosis of cryptococcal meningitis, randomized between 5 February 1987 and 1 January 1990, were included for analysis. InterventionsOral itraconazole (200 mg twice daily), versus amphotericin B (0.3 mg/kg daily) intravenously plus oral flucytosine (150 mg/kg daily) was administered for 6 weeks followed by maintenance therapy with oral itraconazole (200 mg daily) to all patients. Main outcome measuresOutcome measures were a complete or partial response, recrudescence and relapse. ResultsA complete response was observed in five out of the 12 patients who completed 6 weeks of initial treatment with itraconazole versus all 10 patients who completed treatment with amphotericin B plus flucytosine (P = 0.009). A partial response was observed in seven out of the 14 patients assigned to itraconazole. During maintenance therapy, recrudescence (n = 6) or relapse (n = 1) occurred in seven out of the 12 patients initially assigned to itraconazole, whereas two relapses occurred among nine patients initially treated with amphotericin B plus flucytosine (P = 0.22); recurrence of clinical symptoms was significantly related to a positive cerebrospinal fluid culture at 6 weeks (P = 0.003). ConclusionItraconazole is less effective compared with amphotericin B plus flucytosine in achieving a complete response in initial therapy in AIDS patients with cryptococcal meningitis.

Introduction: HIV/AIDS and Aging.

AIDS 2004, 18 (suppl 1):S1–S2This supplement to AIDS is dedicated to research onCNS-related comorbidities and complications in HIV-infected older adults as discussed at the NationalInstitute of Mental Health workshop (‘Mental HealthResearch Issues in HIV Infection and Aging’) held inWashington, D.C., in April, 2002

Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine.

ObjectiveTo assess the HIV-1-RNA response and drug concentrations in cerebrospinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RTV) or SQV/RTV plus stavudine (d4T) in HIV-1-infected patients. DesignA multicentre, open-label, randomized controlled trial. MethodsA total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. ResultsThe median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P = 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P = 0.005). CSF RTV and SQV concentrations were < LLQ in most patients. ConclusionRTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF.

DIFFERENCES IN HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 V3 SEQUENCES FROM PATIENTS WITH AND WITHOUT AIDS DEMENTIA COMPLEX

Paired serum and cerebrospinal fluid (CSF) samples from 10 AIDS patients with and 10 without AIDS dementia complex (ADC) were studied, in an attempt to uncover ADC-associated variation in V3 sequences. Sequences were obtained from four of the patients with and eight of those without ADC. Comparison of the sequences using a resampling technique revealed a significant ADC-associated difference occurring at several amino acid positions. Results from serum and CSF sequences were comparable. These differences may indicate that the virus found in ADC and that in non-ADC patients have different biological properties. Comparison of serum versus CSF sequences within samples from both ADC and non-ADC patients, using the same resampling technique, revealed no clear distinctions. In some patients, the sequence populations in serum and CSF were completely distinct, while in others, there was no difference in distribution. These patterns were not associated with ADC.

Severe neurological complications in association with Epstein-Barr virus infection

Involvement of the nervous system in infectious mononucleosis is common. About 50% have headache on presentation. Neck stiffness without meningitis is a frequent finding. Severe neurological complications are rare though, occurring in fewer than 0.5%. We describe two patients with unusual and severe neurological complications in association with serological evidence of EBV-infection: a 32-year old female developed a bilateral optic neuritis combined with a transverse myelitis and a 72-year old man developed mononeuritis multiplex, autonomic neuropathy and a salt-wasting nephropathy.