Juan Carlos López Bernaldo de Quirós

Visceral Leishmaniasis in Patients Infected with Human Immunodeficiency Virus (HIV)

In an 8-month period nine patients with human immunodeficiency virus (HIV) infection were diagnosed as having visceral leishmaniasis; all diagnoses were based on cultures (eight from bone marrow and one from the skin). Visceral leishmaniasis developed before full-blown acquired immunodeficiency syndrome (AIDS) in seven patients and at the same time as or after AIDS in the other two patients. Three patients had a history of leishmaniasis. Clinical manifestations and laboratory findings were atypical. Leishmania species were cultured from samples taken from all patients; however, six patients had an insignificant antileishmanial antibody titer and Leishmania amastigotes were not seen in their bone marrow smears. Four isolates were identified by isoenzyme analysis as Leishmania donovani infantum. Five patients died, including two patients who had completed at least one 3-week course of therapy with N-methylglucamine antimoniate. Screening should be done for visceral leishmaniasis in patients with HIV infection who live or travel in areas where the disease is endemic. The diagnosis of visceral leishmaniasis may frequently be missed if cultures are not done.

Treatment of Aids-associated progressive multifocal leukoencephalopathy with highly active antiretroviral therapy

Objectives:To evaluate the efficacy of highly active antiretroviral therapy (HAART) in 12 patients with AIDS-associated progressive multifocal leukoencephalopathy (PML). Patients and methods:The diagnosis of PML was established by brain biopsy in six patients and by neuroimaging findings and PCR detection of JC virus in cerebrospinal fluid (CSF) in six patients. We also studied 13 consecutive AIDS patients with biopsy-proven PML cared for in the same institution before HAART was available. Eleven patients of the HAART group and eight patients of the control group received intravenous arabinoside cytosine cycles. Results:With HAART, the median decrease in the HIV viral load was 3.58 log10 copies/ml and the median increase in the CD4 cell count was 74 × 106/l. The median survival time after PML diagnosis was 545 days in the HAART group and 60 days in the control group (P < 0.001, log-rank test). In the HAART group, the neurological deficits improved substantially in six patients and stabilized in six patients. Eleven patients underwent follow-up cranial computed tomography or magnetic resonance scan that showed improvement of PML lesions in 10 patients and stabilization in one patient. Follow-up CSF analysis showed clearance of JC virus in six out of seven patients who had an initial positive result. Conclusions:This study shows that HAART may increase the survival, clinical status and radiological features of AIDS patients with PML. Clearance of JC virus from CSF has been found, suggesting that immune reconstitution can interrupt the JC virus lytic cycle.

Discontinuation of Maintenance Therapy for Cryptococcal Meningitis in Patients with AIDS Treated with Highly Active Antiretroviral Therapy: An International Observational Study

We conducted a retrospective, multicenter study evaluating the safety of discontinuing maintenance therapy for cryptococcal meningitis after immune reconstitution. Inclusion criteria were a previous definitive diagnosis of cryptococcal meningitis, a CD4 cell count of >100 cells/microL while receiving highly active antiretroviral therapy (HAART), and the subsequent discontinuation of maintenance therapy for cryptococcal meningitis. The primary end point was relapse of cryptococcal disease. As of July 2002, 100 patients were enrolled. When maintenance therapy was discontinued, the median CD4 cell count was 259 cells/microL and the median plasma virus load was <2.30 log10 copies/mL, and serum cryptococcal antigen was undetectable in 56 patients. During a median follow-up period of 28.4 months (range, 6.7-64.5; 262 person-years), 4 events were observed (incidence, 1.53 events per 100 person-years; 95% confidence interval, 0.42-3.92). Three of these patients had a CD4 cell count of >100 cells/microL and a positive serum cryptococcal antigen test result during the recurrent episode. In conclusion, discontinuation of maintenance therapy for cryptococcal meningitis is safe if the CD4 cell count increases to >100 cells/microL while receiving HAART. Recurrent cryptococcal infection should be suspected in patients whose serum cryptococcal antigen test results revert back to positive after discontinuation of maintenance therapy.

Safety and immunogenicity of a modified pox vector-based HIV/AIDS vaccine candidate expressing Env, Gag, Pol and Nef proteins of HIV-1 subtype B (MVA-B) in healthy HIV-1-uninfected volunteers: A phase I clinical trial (RISVAC02).

BACKGROUND To investigate the safety and immunogenicity of a modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B), a phase-I, doubled-blind placebo-controlled trial was performed. METHODS 30 HIV-uninfected volunteers at low risk of HIV-1 infection were randomly allocated to receive 3 intramuscular injections (1×10(8)pfu/dose) of MVA-B (n=24) or placebo (n=6) at weeks 0, 4 and 16. All volunteers were followed 48 weeks. Primary end-points were adverse events and immunogenicity. RESULTS A total of 169 adverse events were reported, 164 of grade 1-2, and 5 of grade 3 (none related to vaccination). Overall 75% of the volunteers showed positive ELISPOT responses at any time point. The magnitude (median) of the total responses induced was 288SFC/10(6)PBMC at week 18. Antibody responses against Env were observed in 95% and 72% of vaccinees at week 18 and 48, respectively. HIV-1 neutralizing antibodies were detected in 33% of volunteers. CONCLUSIONS MVA-B was safe, well tolerated and elicited strong and durable T-cell and antibody responses in 75% and 95% of volunteers, respectively. These data support further exploration of MVA-B as an HIV-1 vaccine candidate. Clinical Trials.gov identifier: NCT00679497.

The HIV/AIDS Vaccine Candidate MVA-B Administered as a Single Immunogen in Humans Triggers Robust, Polyfunctional, and Selective Effector Memory T Cell Responses to HIV-1 Antigens

ABSTRACT Attenuated poxvirus vectors expressing human immunodeficiency virus type 1 (HIV-1) antigens are considered promising HIV/AIDS vaccine candidates. Here, we describe the nature of T cell immune responses induced in healthy volunteers participating in a phase I clinical trial in Spain after intramuscular administration of three doses of the recombinant MVA-B-expressing monomeric gp120 and the fused Gag-Pol-Nef (GPN) polyprotein of clade B. The majority (92.3%) of the volunteers immunized had a positive specific T cell response at any time postvaccination as detected by gamma interferon (IFN-γ) intracellular cytokine staining (ICS) assay. The CD4+ T cell responses were predominantly Env directed, whereas the CD8+ T cell responses were similarly distributed against Env, Gag, and GPN. The proportion of responders after two doses of MVA-B was similar to that obtained after the third dose of MVA-B vaccination, and the responses were sustained (84.6% at week 48). Vaccine-induced CD8+ T cells to HIV-1 antigens after 1 year were polyfunctional and distributed mainly within the effector memory (TEM) and terminally differentiated effector memory (TEMRA) T cell populations. Antivector T cell responses were mostly induced by CD8+ T cells, highly polyfunctional, and of TEMRA phenotype. These findings demonstrate that the poxvirus MVA-B vaccine candidate given alone is highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4 and CD8 T cell responses to HIV-1 antigens, with preference for TEM. Thus, on the basis of the immune profile of MVA-B in humans, this immunogen can be considered a promising HIV/AIDS vaccine candidate.

The Eldest of Older Adults Living with HIV: Response and Adherence to Highly Active Antiretroviral Therapy

OBJECTIVE The study objective was to analyze the characteristics and the response to therapy in the eldest of the older adults living with human immunodeficiency virus. METHODS The study included a cohort of patients with human immunodeficiency virus aged 55 years or more on initiating highly active antiretroviral therapy (HAART). Immunologic and virologic response, morbidity, and mortality were assessed. Patients were categorized as aged less than 65 years and 65 years or more. RESULTS A total of 112 patients were included (82 patients aged<65 years and 30 patients aged> or =65 years). There were no differences between the age groups in baseline characteristics, survival, and virologic response. There was a trend toward better adherence and a lower CD4+ cell increase after HAART in the older group. CONCLUSION A relationship was found between lower CD4+ cell increase after HAART and advanced age. We found the best adherence to treatment in the eldest of the older adults, and this has been shown to be the only protective independent factor related to virologic failure.

Resistance and virulence mutations in patients with persistent infection by pandemic 2009 A/H1N1 influenza

BACKGROUND Pandemic 2009 influenza A/H1N1 (H1N1v) is resistant to adamantanes, leaving neuraminidase inhibitors as the only therapeutic option. Other mutations are considered to be associated with virulence and clinical severity. However, out of the surveillance programs, few studies analyze the presence of resistance/virulent H1N1v variants in certain clinical circumstances. OBJECTIVES To define the frequency and role of resistance and virulence mutations in a specific clinical circumstance-in patients with persistent infection by H1N1v. STUDY DESIGN Observational study of patients with persistent H1N1v infection admitted to our hospital. RESULTS NAI-resistance mutations were detected in 14.3% of cases with persistent infection (2/14), and in none of the non-persistent controls (0/15). These cases were initially infected with susceptible variants that acquired resistance at different time-points after therapy with oseltamivir (OTV). The first case (case 2) was an HIV-positive patient who rapidly acquired resistance 9 days after diagnosis (6 days on OTV) and whose infection resolved after standard OTV therapy. The second case (case 3) was a patient with chronic lymphocytic leukemia [corrected] and the longest viral persistence (59 days). The resistance mutation was detected in the specimen taken on day 37 after diagnosis (30 days on OTV). Once the resistance mutation was identified, OTV was substituted by zanamivir and the infection resolved. In addition to mutations encoding resistance, variants associated with virulence were also sought. The D225G mutation was not found in any case, whereas the D225E variant was identified in three persistent cases but also in two non-persistent ones. In one patient, the D225E substitution coincided with the H275 resistant mutation. CONCLUSIONS NAI-resistance mutations were detected, at rather different paces, in non-severe immunosuppressed cases with persistent infection by influenza A/H1N1v.

Prevención de las infecciones oportunistas en pacientes adultos y adolescentes infectados por el VIH. Recomendaciones de GESIDA/Plan Nacional sobre el Sida

Objetivo Actualizacion de las recomendaciones del Grupo de Estudio de Sida (GESIDA) y la Secretaria del Plan Nacional sobre el Sida (PNS) sobre prevencion de las infecciones oportunistas en pacientes adultos y adolescentes infectados por el virus de la inmunodeficiencia humana (VIH). Metodos Las recomendaciones han sido consensuadas por un grupo de expertos de GESIDA y/o del PNS tras la revision del antiguo documento y las aportaciones cientificas sobre la materia de los ultimos anos. Para la clasificacion de la fuerza y de la calidad de las recomendaciones se ha seguido el sistema utilizado por la Sociedad Americana de Enfermedades Infecciosas (IDSA) y el Servicio de Salud Publica de los Estados Unidos de America (USPHS). Resultados En este documento, se realiza una revision pormenorizada de las medidas para prevenir las infecciones causadas por virus, bacterias, hongos y parasitos en el contexto de la infeccion por el VIH. Para cada grupo de patogenos se han dado recomendaciones para prevenir la exposicion a los mismos, para las profilaxis primarias y para las profilaxis secundarias. Tambien se han establecido unos criterios para la retirada de las profilaxis en pacientes que tienen una buena respuesta al tratamiento antirretroviral de gran actividad (TARGA). Conclusiones El TARGA es la mejor estrategia para prevenir las infecciones oportunistas en pacientes infectados por el VIH. Sin embargo, las profilaxis continuan siendo necesarias en los paises con pocos recursos economicos, en pacientes muy inmunodeprimidos hasta que el TARGA logra sus efectos, en los que no desean o no pueden tomar TARGA, en aquellos en los que este fracasa y en el pequeno grupo de infectados que son incapaces de recuperar cifras adecuadas de linfocitos T CD4+ a pesar de una buena inhibicion de la replicacion del VIH.

Ciprofloxacin in patients with bacteremic infections

Abstract The efficacy and safety of ciprofloxacin in the treatment of 68 episodes of bacteremia were studied. Patients were treated intravenously (30 cases), orally (13 cases), or with sequential intravenous/oral therapy (25 cases). Intravenous doses ranged from 200 to 400 mg per day and oral doses ranged from 1,000 to 1,500 mg per day. According to the criteria of McCabe and Jackson, 39 cases had nonfatal and 29 had ultimately fatal underlying diseases. The clinical condition of patients at the start of therapy was critical or poor in 40 cases and fair or good in 28. Sixty-four of the 68 episodes of bacteremia were monomicrobial and the remaining four were polymicrobial. The causative micro-organisms were: Escherichia coli (18 episodes), Pseudomonas aeruginosa (13 episodes), Acinetobacter sp. (10 episodes), Salmonella sp. (seven episodes), Enterobacter sp. (six episodes), Proteus sp. (four episodes), Serralia sp. (four episodes), Haemophilus influenzae (three episodes), Klebsiella sp. (three episodes), Staphylococcus aureus (2 episodes), and Morganella morganii (two episodes). Overall clinical efficacy of ciprofloxacin was 94 percent (64 of 68 patients). Bacteremia persisted in four patients (failure rate of 6 percent). Five organisms persisted: Acinetobacter sp. (two patients), P. aeruginosa (one patient), Enterobacter sp. (one patient), and Serratia sp. (one patient). Side effects were phlebitis associated with intravenous administration (four cases), dizziness (four cases), and superinfection (six cases). Superinfecting organisms and sites were as follows: Enterococcus faecalis , wound (2 cases); Candida sp., urinary tract infection (one case); Acinetobacter anitratus (ciprofloxacin resistant), urinary tract infection (one case); Staphylococcus epidermidis , blood (one case); and Clostridium perfringens , blood (one case). Ciprofloxacin administered either intravenously, orally, or intravenously followed by the oral route is effective therapy in the treatment of severe bacteremic infections.

Lipid and Apoprotein Profile in Hiv-1-infected Patients After Cd4-guided Treatment Interruption

Objectives:The aims of the present study were to determine if metabolic abnormalities and cytokine derangements are modified in HIV-1-infected patients after 12 months on treatment interruption (TI). Design:The design of this study was prospective randomized study. Methods:Longitudinal multicenter study in HIV-1-infected patients with a 12-month follow-up. Patients on stable highly active antiretroviral therapy, with CD4 count >600/μL and HIV RNA <50 copies/mL for at least 6 months, were randomized to interrupt therapy or continue ongoing highly active antiretroviral therapy. Lipids (total cholesterol, triglycerides), apoproteins (A1, B, and E), and adipocytokines (leptin, adiponectin, plasminogen activator inhibitor-1, monocyte chemotactic protein-1, Interleukin-6, Interleukin-8, and tumor necrosis factor-α) were measured at baseline and at month 12. Multiplex suspension bead array immunoassay was performed using the Luminex 100 analyzer to identify protein expression in plasma. Results:Patients who underwent TI (n = 19) had a significant decrease in median cholesterol levels (P < 0.001), while median triglyceride levels remained unchanged. There was a significant decrease in Apo-A1 levels (P = 0.048) and Apo-B levels (P < 0.001) and an increase in tumor necrosis factor-α levels (P = 0.034). Given the greater decrease in Apo-B, the ratio Apo-A1/Apo-B increased after 12 months of TI (from 3.4 to 5.1, P = 0.008). We did not find significant variations in leptin or adiponectin levels. In patients who continued on highly active antiretroviral therapy (n = 18), there were no significant changes in any of the measured parameters. Conclusion:The lipid profile and apoproteins levels change toward a less atherogenic profile after TI, arguing against a lipid-mediated mechanism to explain the increased cardiovascular risk in patients who interrupt treatment.