Hepatitis B virus compartmentalization in the cerebrospinal fluid of HIV-infected patients.

We detected hepatitis B virus (HBV) DNA in the cerebrospinal fluid (CSF) of 26 adolescents co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) with neurological disease and studied compartmentalization of HBV in the CSF. More than half of the subjects with positive HBV DNA plasma also had CSF positive for HBV. CSF HBV DNA was found in subjects with preserved blood-brain barrier integrity. In a subgroup of these subjects, compartmentalized evolution of HBV was demonstrated by distinct profiles of resistance mutations. Future studies are warranted to determine the clinical significance of HBV presence in the CSF and its contribution to HIV-associated neurological disease.

Major HIV resistance mutations in untreated Romanian patients.

Drug resistance mutations are frequently detected in antiretroviral-naive HIV positive patients, however the data on transmitted resistance in non-B subtypes are limited. As HIV1 subtype F is prevalent in Romania, our goal is to analyze resistance mutations in the pol gene of HIV-1 isolates from drug-naive Romanian patients. HIV-1 pol gene from 12 untreated patients, newly diagnosed (n = 6) and chronically infected (n=6), with detectable HIV RNA viral load was genotyped and the viral subtype was determined by using the Stanford database algorithm. 8/12 strains belonged to the F subtype, 1/12 to the G subtype, and the rest of the studied strains appeared to be K/F, A/F and J/F inter-subtype recombinant forms. The prevalence of HIV-1 strains with at least one major drug resistance mutation in the studied group was unexpectedly high. Major mutations associated with NRTI, NNRTI and PI resistance were detected in 6/12 patients, 2/12 patients and 3/12 patients, respectively; in addition all viral strains had minor mutations in the protease gene. Newly diagnosed patients harbored resistant variants more often than chronically infected ones (4/6 vs. 2/6) did. These data support the use of genotypic resistance testing in treatment-naive HIV positive patients, in order to guide the selection of the first line of antiretrovirals, due to the fact that persons with transmitted drug resistance have a higher risk for both virologic failure and development of resistance at treatment initiation.

How much do antiretroviral drugs penetrate into the central nervous system?

The central nervous system can act as a compartment in which HIV can replicate independently from plasma, and also as a sanctuary in which, under suboptimal drug pressure, HIV antiretroviral genetic variants can occur. Continuous replication of HIV in brain can contribute to neurocognitive impairment. Therefore, reaching adequate concentrations of antiretrovirals in the central nervous system might be essential in providing neuroprotection and improving neurocognition. Antiretrovirals have a restricted entry into the brain, due to several factors: the unique structure of the blood-brain barrier, and the existence of efficient efflux mechanisms. However, there is a high variability of antiretrovirals in reaching therapeutic drug concentrations in cerebrospinal fluid, that depend on the characteristics of the antiretrovirals (molecular weight, lipophilicity, protein binding) and on their capacity to be substrate for efflux transporters. The review aims to discuss the main mechanisms that interfere with antiretroviral penetration into central nervous system, and to summarize the current data concerning the penetrability of different antiretrovirals into the cerebrospinal fluid.

Long-term efficacy and safety of fosamprenavir plus ritonavir versus lopinavir/ritonavir in combination with abacavir/lamivudine over 144 weeks.

PURPOSE: The KLEAN study extension assessed the long-term efficacy and safety of fosamprenavir-ritonavir (FPV/r) and lopinavir-ritonavir (LPV/r), both administered with abacavir/lamivudine (ABC/3TC) fixed dose combination, over 144 weeks. METHODS: KLEAN was an open-label, noninferiority study that randomised antiretroviral-naïve patients to FPV/r twice daily (bid) or LPV/r bid with ABC/3TC once daily (qd). Patients with a viral load of <400 copies/mL at Week 48 were eligible to participate in the KLEAN study extension (up to 144 weeks) and continued with their previously randomised therapy. RESULTS: The KLEAN study extension (48 to 144 weeks) randomized 199 patients. The proportion of TLOVR responders (HIV-1 RNA <50 copies/mL) at Week 144 was 73% and 60% in the FPV/r and LPV/r arms, respectively. The proportion of TLOVR responders (<50 copies/mL) was the same irrespective of baseline HIV-1 RNA (>100,000 or 100,000 copies/mL). The Week 144 median (interquartile range) change from baseline CD4+ cell count was 300 (236-433) cells/mm3 and 335 (225-444) cells/mm3 in the FPV/r and LPV/r arms, respectively. Diarrhea was the most frequently reported adverse event. A small proportion of patients (FPV/r, 13%; LPV/r, 9%) discontinued study medication due to adverse events. Three patients (FPV/r, 1; LPV/r, 2) experienced virological failure between Week 48 and Week 144. CONCLUSION: The findings of the KLEAN study extension (48 to 144 weeks) support durable viral suppression with both FPV/r and LPV/r treatment regimens when used in combination with ABC/3TC irrespective of viral load at baseline. Both regimens were well tolerated and had similar safety profiles.

Phagocytic function of monocytes in children with human immunodeficiency virus type 1 infection.

We investigated the phagocytic function of monocytes in 7- to 10-year-old children horizontally infected with human immunodeficiency virus type 1 (HIV-1) in comparison to that in healthy sex- and age-matched controls. CR3-mediated phagocytosis was increased in patients with HIV-associated pulmonary tuberculosis, independently of CD4 counts and p24 antigenemia.

Clinical manifestations in the West Nile virus outbreak.

During the summer of 1996 an unusual clustering of meningoencephalitis cases was recorded in the Capital City, Bucharest, and in some areas from South-East Romania. After an initial suspicion of an enteroviral etiology was discarded, the West Nile etiology was confirmed by specific antibodies demonstration through hemagglutination-inhibition and ELISA tests. This study included 251 patients with the diagnoses of West Nile acute encephalitis (166 cases), acute meningitis (57 cases) and acute febrile disease (33 cases). The patients' age ranged from 1 to 89 years (mean 51.1 years). The most frequent clinical manifestations were: fever (95.7% of cases), cephalalgia (92.6%), stiffness of the neck (89.1%), vomiting (62.5%), marked asthenia (46.5%), myalgia (28.9%). In addition, patients with encephalitis exhibited: alteration of consciousness (89.2% of cases), tremor of extremities (40.4%), ataxia (44%), paralysis (15.1%). The fatality rate was 15.1% in acute encephalitis, 1.8% in acute meningitis and 0% in the acute febrile disease.

Clinical and immunological correlates of immune-complex-dissociated HIV-1 p24 antigen in HIV-1-infected children.

It has been reported that HIV-1 p24 antigen (p24 Ag) detection is improved after dissociation of immune complexes using acid treatment (ICD assay). In order to evaluate the clinical significance of p24 Ag detected by the standard assay and by the ICD assay in pediatric patients, we related these measurements to clinical status, level of p24 antibody, and percentage of CD4+ lymphocytes. Fifty-nine plasma specimens from 20 symptomatic HIV-1-infected children, collected prospectively over a 1-year period, were tested for these markers. Plasma was collected at the beginning of zidovudine therapy and approximately 7 and 12 months thereafter. Compared with the standard assay, the ICD assay showed a higher number of samples positive for p24 Ag (78% versus 34%) and an increase in the levels of p24 Ag (median value of 129 versus 24 pg/ml). The anti-p24 antibody level was inversely correlated with the p24 Ag level measured by either assay. Four children negative for p24 Ag by both assays had a stable clinical course. In contrast, 50% of the children negative by the standard assay but positive for ICD p24 Ag and 75% of the children positive by both assays had progression of disease. No patients were positive by the standard assay but negative by the ICD assay. Children whose plasma tested positive by both assays had lower percentages of lymphocytes that were CD4+ by comparison with children who were negative by both assays; children whose plasma tested positive only by the ICD assay formed an intermediate group.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigations on HBe antigen. Note III. HBe system and sex-dependent clearance of HBsAg subtypes.

The presence of HBeAg and anti-HBe was tested in 876 serum samples collected at 10-day intervals from 146 HBsAg-positive acute viral hepatitis patients. The clearance of HBsAg was followed up in the patients grouped according to HBsAg subtypes and to HBe system seroconversion or HBeAg persistence. The clearance of HBsAg was found to be more rapid in patients with HBe system seroconversion, in the case of HBsAg/ay and in female patients.