S. Moreno

A SHORT-TERM STUDY OF THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF RITONAVIR, AN INHIBITOR OF HIV-1 PROTEASE

BACKGROUND Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability. METHODS We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. RESULTS During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment. CONCLUSIONS In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established.

The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals

Objective:To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. Design:A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. Results:Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41–0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22–0.37) for less than 100 cells/μl, 0.33 (0.25–0.44) for 100 to less than 200 cells/μl, 0.38 (0.28–0.52) for 200 to less than 350 cells/μl, 0.55 (0.41–0.74) for 350 to less than 500 cells/μl, and 0.77 (0.58–1.01) for 500 cells/μl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49–0.67) for less than 1 year since initiation to 0.21 (0.14–0.31) for 5 years or more (P value for trend <0.001). Conclusion:We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

Comparative study of mupirocin and oral co-trimoxazole plus topical fusidic acid in eradication of nasal carriage of methicillin-resistant Staphylococcus aureus.

Mupirocin is a topically applied drug that is very active in the eradication of nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA). However, studies designed to compare mupirocin treatment with other antimicrobial regimens are lacking. We therefore conducted an open, prospective, randomized, controlled trial to compare the efficacy and safety of mupirocin versus those of oral co-trimoxazole plus topical fusidic acid (both regimens with a clorhexidine scrub bath) for the eradication of MRSA from nasal and extranasal carriers of MRSA. The eradication rates with mupirocin and co-trimoxazole plus fusidic acid at 2, 7, 14, 21, 28, and 90 days were 93 and of 93, 100 and 100, 97 and 94, 100 and 92, 96 and 95, and 78 and 71%, respectively, for nasal carriage. At 7, 14, and 28 days the eradication rates for extranasal carriage by the two regimens were 23 and 74, 83 and 76, and 45 and 69%, respectively. The efficacies and safety of both regimens were similar. The MRSA isolates were not resistant to the study drugs either at the baseline or at follow-up. These results suggest that mupirocin and co-trimoxazole plus fusidic acid, both used in conjunction with a chlorhexidine soap bath, are equally effective and safe for the eradication of MRSA from nasal and extranasal MRSA carriers. Mupirocin was easier to use but was more expensive.

Cohorte RIS de pacientes con infección por VIH sin tratamiento antirretroviral previo (CoRIS): metodología y primeros resultados

Objetivo Describir la metodologia y los resultados basales de la cohorte de pacientes con infeccion por virus de la inmunodeficiencia humana (VIH) de la Red de Investigacion de Sida (CoRIS). Metodos Cohorte abierta, prospectiva, multicentrica, de pacientes mayores de 13 anos con diagnostico de VIH sin tratamiento antirretroviral previo. La seleccion se realizo entre enero de 2004 y octubre de 2005 en 17 hospitales de 8 comunidades autonomas. Se recogieron variables sociodemograficas, epidemiologicas, clinicas y analiticas, junto con muestras biologicas iniciales y de seguimiento. Resultados Se han incluido 1.591 pacientes, 24% mujeres, mediana de edad 36 anos, el 74% diagnosticados de VIH en 2004 o 2005. El 27% provenian de otros lugares de origen, destacando Latinoamerica (16%) y Africa subsahariana (5%). El 32% tenian estudios secundarios y el 16% universitarios. La categoria de transmision mas frecuente fue la de hombres homosexuales (37%), seguida por la heterosexual (36%); y solo el 21% tenian antecedente de consumo de drogas inyectadas. Al ingreso en la cohorte la mediana de CD4 era 317 celulas/μl, la de carga viral 52.300 copias/ml y el 18% tenian diagnostico de sida. Las enfermedades diagnosticas de sida mas frecuentes fueron: neumonia por Pneumocystis jiroveci (6,1%), candidiasis esofagica (3,3%) y tuberculosis extrapulmonar (3,0%) y pulmonar (2,7%). Se registraron 35 fallecimientos (2,2%). El 33% de los pacientes han aportado muestras basales al BioBanco. Conclusiones CoRIS proporciona informacion relevante del perfil epidemiologico reciente de la infeccion por el VIH en nuestro medio, en el que predomina la transmision sexual. Se demuestra la viabilidad de esta cohorte, recogiendo datos clinicos y epidemiologicos junto con muestras biologicas, lo que abre grandes posibilidades de investigacion.

Group A streptococcal bacteremia : a 10-year prospective study

&NA; Abbreviations used in this article: GAS, group A Streptococcus; IVDU, intravenous drug users; non‐IVDU, non‐intravenous drug users; STSS, Streptococcal toxic shock syndrome.

Genome wide DNA-profiling of HIV-related B-cell lymphomas

Non‐Hodgkin lymphomas (NHL) represent a frequent complication of human immunodeficiency virus (HIV) infection. To elucidate HIV‐NHL pathogenesis, we performed a genome‐wide DNA profiling based on a single nucleotide polymorphism‐based microarray comparative genomic hybridization in 57 HIV‐lymphomas and, for comparison, in 105 immunocompetent diffuse large B‐cell lymphomas (IC‐DLBCL). Genomic complexity varied across HIV‐NHL subtypes. HIV‐Burkitt lymphoma showed a significantly lower number of lesions than HIV‐DLBCL (P = 0·032), whereas the median number of copy number changes was significantly higher in Epstein–Barr virus negative (EBV‐) HIV‐DLBCL (42·5, range 8–153) compared to EBV+ cases (22; range 3–41; P = 0·029). Compared to IC‐DLBCL, HIV‐DLBCL displayed a distinct genomic profile with no gains of 18q and specific genetic lesions. Fragile sites‐associated genes, including FHIT (FRA3B), WWOX (FRA16D), DCC (FRA18B) and PARK2 (FRA6E) were frequently inactivated in HIV‐NHL by interstitial deletions, and a significantly higher prevalence of FHIT alterations was observed in HIV‐DLBCL compared to IC‐DLBCL. The same genes involved by fragile site deletions were also frequently affected by aberrant methylation of regulative regions.

Relapsing Visceral Leishmaniasis in HIV-Infected Patients Undergoing Successful Protease Inhibitor Therapy

Abstract The aim of this study was to establish the evolution of visceral leishmaniasis (VL) in 10 consecutive patients coinfected with VL and HIV, taking into account the decline in the incidence of opportunistic infections after the introduction of protease inhibitor therapy. During a median follow-up of 31 months, 7 (70%) of 10 patients relapsed. The incidence of relapse was slightly lower than before institution of protease inhibitor therapy (20 vs. 13 patient-months), with a 31% probability that relapse would not have taken place within 2 years. VL relapses occurred even though increases in the CD4+ cell counts were observed and HIV loads were undetectable, suggesting that successful antiretroviral therapy is not sufficient to control the disease. Relapsing patients also had a lower increase in the CD4+ cell count.

LEUCONOSTOC SPECIES AS A CAUSE OF BACTEREMIA : TWO CASE REPORTS AND A LITERATURE REVIEW

Two new cases of significant bacteremia caused byLeuconostoc spp. are reported and five others described in the literature are reviewed. Four of the seven patients were under one year old and presented with prolonged diarrhea related to gastrointestinal disorders. The remaining three patients were over 50 years of age and being treated in intensive care units. Six patients had nosocomially acquired catheter-related bacteremia.Leuconostoc spp. are naturally resistant to vancomycin, and five patients had received this antibiotic for prior bacteremia caused by methicillin-resistant staphylococci. The majority of patients presented with fever without severe complications. Penicillin is the treatment of choice and there is no report of any death directly attributable to infection by these microorganisms. Infection withLeuconostoc spp. should be suspected if “vancomycin-resistant streptococci” are isolated from the blood, and recorded as a potential cause of bacteremia in patients with indwelling intravenous catheters.

Genomic profiling of Richter's syndrome: recurrent lesions and differences with de novo diffuse large B-cell lymphomas.

Richters syndrome (RS) represents the transformation of chronic lymphocytic leukaemia (CLL) to aggressive lymphoma and is mostly represented by diffuse large B‐cell lymphoma (DLBCL), with a post‐germinal centre (GC) phenotype, clonally related to the pre‐existing CLL. RS has a very poor prognosis and its pathogenetic mechanisms are poorly understood. In order to gain additional hints in RS pathogenesis, we performed a genome‐wide DNA profiling study of 13 RS phases and eight matched CLL phases using the Affymetrix Human Mapping 250K NspI SNP arrays. Individual genomic profiles were heterogeneous, with no individual lesions occurring in more than half of the cases. However, several observations suggest that MYC pathway might be involved in RS. The 13q13.3‐qter region containing MIRHG1 (MIR‐17‐92), a cluster of microRNA interacting with c‐MYC, was acquired at the time of transformation. The 13q gain was coupled with the gain of c‐MYC and loss of TP53. Translocation of c‐MYC was acquired at transformation in a fraction of cases and this event appeared mutually exclusive with gain of MIRHG1. MYCN, a c‐MYC homologue, was also recurrently gained. By comparing RS with 48 de novo DLBCL, RS presented a significantly lower prevalence of deletions affecting the PRDM1 and TNFAIP3, genes on 6q, known to be associated with a post‐GC phenotype. In conclusion, the genomic profile of RS seems to differ from what observed in de novo DLBCL and in other transformed DLBCL. Genomic lesions occurring in RS are heterogeneous suggesting the existence of different RS subsets, possibly due to different transforming mechanisms. A deregulation of MYC pathway might represent one of the main transformation events in the pathogenesis of a subset of RS clonally related to the previous CLL. Copyright

Single nucleotide polymorphism-arrays provide new insights in the pathogenesis of post-transplant diffuse large B-cell lymphoma

Post‐transplant lymphoproliferative disorders (PTLD) are complications of solid organ transplantation associated with severe morbidity and mortality. Diffuse large B‐cell lymphoma (DLBCL) represents the most common form of monomorphic PTLD. We studied 44 cases of post‐transplant DLBCL (PT‐DLBCL) with high‐density genome wide single nucleotide polymorphism‐based arrays, and compared them with 105 cases of immunocompetent DLBCL (IC‐DLBCL) and 28 cases of Human Immunodeficiency Virus‐associated DLBCL (HIV‐DLBCL). PT‐DLBCL showed a genomic profile with specific features, although their genomic complexity was overall similar to that observed in IC‐ and HIV‐DLBCL. Among the loci more frequently deleted in PT‐DLBCL there were small interstitial deletions targeting known fragile sites, such as FRA1B, FRA2E and FRA3B. Deletions at 2p16.1 (FRA2E) were the most common lesions in PT‐DLBCL, occurring at a frequency that was significantly higher than in IC‐DLBCL. Genetic lesions that characterized post‐germinal center IC‐DLBCL were under‐represented in our series of PT‐DLBCL. Two other differences between IC‐DLBCL and PT‐DLBCL were the lack of del(13q14.3) (MIR15/MIR16) and of copy neutral LOH affecting 6p [major histocompatibility complex (MHC) locus] in the latter group. In conclusion, PT‐DLBCL presented unique features when compared with IC‐DLBCL. Changes in PT‐DLBCL were partially different to those in HIV‐DLBCL, suggesting different pathogenetic mechanisms in the two conditions linked to immunodeficiency.