Antiretroviral concentrations and surrogate measures of efficacy in the brain tissue and CSF of preclinical species.

1. Antiretroviral concentrations in cerebrospinal fluid (CSF) are used as surrogate for brain tissue, although sparse data support this. We quantified antiretrovirals in brain tissue across preclinical models, compared them to CSF, and calculated 90% inhibitory quotients (IQ90) for nonhuman primate (NHP) brain tissue. Spatial distribution of efavirenz was performed by mass-spectrometry imaging (MSI). 2. HIV or RT-SHIV-infected and uninfected animals from two humanized mouse models (hemopoietic-stem cell/RAG2-, n = 36; bone marrow-liver-thymus/BLT, n =13) and an NHP model (rhesus macaque, n =18) were dosed with six antiretrovirals. Brain tissue, CSF (NHPs), and plasma were collected at necropsy. Drug concentrations were measured by LC-MS/MS. Rapid equilibrium dialysis determined protein binding in NHP brain. 3. Brain tissue penetration of most antiretrovirals were >10-fold lower (p < 0.02) in humanized mice than NHPs. NHP CSF concentrations were >13-fold lower (p <0.02) than brain tissue with poor agreement except for efavirenz (r = 0.91, p = 0.001). Despite 97% brain tissue protein binding, efavirenz achieved IQ90>1 in all animals and 2-fold greater white versus gray matter concentration. 4. Brain tissue penetration varied across animal models for all antiretrovirals except raltegravir, and extrapolating brain tissue concentrations between models should be avoided. With the exception of efavirenz, CSF is not a surrogate for brain tissue concentrations.

Cryptoccocal meningitis in Yaoundé (Cameroon) HIV infected patients: Diagnosis, frequency and Cryptococcus neoformans isolates susceptibility study to fluconazole.

Cryptococcal meningitis is a mycosis encountered especially in patients with Acquired Immunodeficiency Syndrome and is fatal in the absence of treatment. Information on epidemiology, diagnosis and susceptibility profile to antifungal drugs, are scarce in Cameroon. Authors evaluated the diagnosis possibilities of the cryptococcal meningitis in Cameroon, and studied the antifungal susceptibility of isolated strains to fluconazole, used as first line treatment of the disease in Cameroon. Between December 2009 and July 2011, 146 cerebrospinal fluids obtained from HIV patients with suspicion of meningitis were analysed. The diagnosis procedure involved macroscopic and cyto-chemical analysis, India ink test, culture on Sabouraud chloramphenicol medium and antigen latex agglutination test. Antifungal susceptibility testing of isolated strains to fluconazole was done by the E-test(®) method. The diagnosis of cryptococcal meningitis gave 28.08% positive cases. Among these patients, 80% were at stages III and IV and 20% at stage I of the HIV infection, according to the WHO previous classification. Cyto-chemical analysis showed current findings in the case of cryptococcal meningitis. India ink test and latex agglutination test exhibited very high sensitivity and specificity (>94%). Fluconazole antifungal susceptibility testing gave MICs lower than 32µg/mL to 92.7% of isolated strains and MICs greater than this value to 7.3% of isolates. These results showed that cryptococcal meningitis remains a real problem among HIV infected patients in Yaoundé. The emergence of fluconazole reduced susceptibility strains is worrying. Nevertheless, efficacy of rapid detection tests is interesting because this will help in rapid diagnosis and treatment of patients.

Oral doxycycline for treatment of neurosyphilis in two patients infected with human immunodeficiency virus.

The frequency of syphilis has been increasing during the past 5 years primarily among men who have sex with men, many of whom are infected with the human immunodeficiency virus (HIV). Data on treatment options other than intravenous or intramuscular penicillin for syphilis are very limited. We describe two HIV-infected patients with asymptomatic neurosyphilis who were successfully treated with oral doxycycline. The first patient was a 45-year-old Hispanic man with well-suppressed HIV RNA who had a positive Venereal Disease Research Laboratory (VDRL) titer of 1:128. His cerebral spinal fluid (CSF) revealed a positive VDRL titer of 1:16, and an elevated white blood cell count of 96 cells/mm(3) and protein level of 89 mg/dl. He received high-dose doxycycline 200 mg twice/day for 28 days. Two months later, his CSF VDRL titer, white blood cell count, and protein level decreased to 1:4, 5 cells/mm(3), and 60 mg/dl, respectively. The second patient was a 37-year-old Caucasian man with complications from acquired immunodeficiency disease. A routine VDRL titer was found to be 1:64. Although the CSF VDRL was nonreactive, both his white blood cell count and protein level were elevated at 29 cells/mm(3) and 46 mg/dl, respectively. High-dose doxycycline 200 mg twice/day was prescribed for 28 days. Three months later, the patient's VDRL titer decreased to 1:2; his CSF white blood cell count decreased significantly to 1 cell/mm(3), and his protein level was within normal limits. Clinicians should be aware that an extended course of high-dose, oral doxycycline may be an effective and safe alternative regimen to intravenous or intramuscular penicillin, without requiring hospitalization or home health care, for the treatment of neurosyphilis in HIV-infected patients. Prospective trials are needed to assess the long-term efficacy oral doxycycline for neurosyphilis.

Failure of atorvastatin to modulate CSF HIV-1 infection: results of a pilot study.

BACKGROUND: HIV-1 infection of the CSF space is nearly universal in untreated systemic infection, and correlates strongly with intrathecal and systemic immunoactivation and CSF pleocytosis. Based on the potential immunomodulatory and antiviral properties of HMG-CoA reductase inhibitors (statins), we examined the effect of atorvastatin on CSF HIV-1 infection and associated CSF abnormalities in a small pilot study. METHODS: Seven male HIV-1-infected, antiretroviral-naïve subjects with a mean blood CD4+ T cell count of 473 cells/muL were studied in an open-label, single-arm pilot study to assess the effects of 80 mg atorvastatin daily for 8 weeks. The primary endpoint was the change in CSF HIV-1 RNA levels, both absolutely and relative to plasma HIV-1 RNA, at 4 and 8 weeks of treatment. Other outcome measures included CSF white blood cell counts and neopterin concentrations as indices of intrathecal immunoactivation, and blood HIV-1 RNA levels, neopterin concentrations, and T lymphocyte counts. Effects on blood lipids were used to monitor the established biologic effects of atorvastatin and treatment adherence. RESULTS: No significant changes in CSF virologic and inflammatory indices or in systemic HIV-1 infection were observed during atorvastatin treatment despite potent reduction of blood lipids. CONCLUSION: Atorvastatin showed no appreciable effect on CSF HIV-1 infection or intrathecal immunoactivation in this small uncontrolled study and thus appears to have little promise as an immunomodulatory adjuvant therapy for CNS HIV-1 infection, at least in neuroasymptomatic subjects with preserved CD4+ T cell counts.

CSF quinolinic acid levels are determined by local HIV infection: cross-sectional analysis and modelling of dynamics following antiretroviral therapy.

Quinolinic acid (QUIN) is a product of tryptophan metabolism that can act as an endogenous brain excitotoxin when released by activated macrophages. Previous studies have shown correlations between increased CSF QUIN levels and the presence of the AIDS dementia complex (ADC), a neurodegenerative condition complicating late-stage human immunodeficiency virus type 1 (HIV) infection in some patients. CSF QUIN is putatively one of the important molecular mediators of the brain injury in this clinical setting and, more generally, serves as a marker of local macrophage activation. This study was undertaken to examine the relationship of CSF QUIN concentrations to local HIV infection and to define the effects of antiretroviral drug treatment on CSF QUIN using two complementary approaches. The first was an exploratory cross-sectional analysis of a clinically heterogeneous sample of 62 HIV-infected subjects, examining correlations of CSF QUIN levels with CSF and plasma HIV RNA levels and other salient parameters of infection. The second involved longitudinal observations of a subset of 20 of these subjects who initiated new antiretroviral therapy regimens. In addition to descriptive analysis, we used kinetic modelling of QUIN decay in relation to that of HIV RNA to assess further the relationship between CSF QUIN and infection in the dynamic setting of treatment. The cross-sectional studies showed strong correlations of CSF QUIN with both CSF HIV RNA and blood QUIN levels, as well as with elevations in CSF white blood cells, CSF total protein and CSF:blood albumin ratio. In this group of subjects with a low incidence of active, untreated ADC, CSF QUIN did not correlate with ADC stage or measures of quantitative neurological performance. Antiviral treatment reduced the CSF QUIN levels in all the longitudinally followed, treated subjects. Kinetic modelling of CSF QUIN decay indicated that CSF QUIN levels were driven primarily by CSF HIV infection with a lesser contribution from blood QUIN levels. In three subjects with new-onset, untreated ADC, CSF QUIN decay paralleled both CSF HIV decrement and improvement in neurological performance. These studies show that CSF QUIN concentrations relate primarily to active CSF HIV infection and to a lesser extent to plasma QUIN. CSF QUIN serves as a marker of local infection with a wide dynamic range. The time course of therapy-induced changes links CSF QUIN to local infection and supports the action of antiviral therapy in ameliorating immunopathological brain injury and ADC.