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Cahn P.,Fundacion Huesped | Pozniak A.L.,Chelsea and Westminster Hospital NHS Foundation Trust | Mingrone H.,Fundacion IDEAA | Brites C.,Federal University of Bahia | And 16 more authors.
The Lancet | Year: 2013

Background Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral- experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. Methods ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. Findings Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3·7%, 95% CI -6·1 to -1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir). Interpretation Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group. Funding ViiV Healthcare. © 2013 Elsevier Ltd.


de Souza Cavalcanti J.,Instituto Adolfo Lutz | de Paula Ferreira J.L.,Instituto Adolfo Lutz | de Souza Guimaraes P.M.,Instituto Adolfo Lutz | Vidal J.E.,Institute Infectologia Emilio Ribas | de Macedo Brigido L.F.,Instituto Adolfo Lutz
Journal of Antimicrobial Chemotherapy | Year: 2015

Objectives: Dolutegravir is a second-generation integrase strand transfer inhibitor (InSTI) that has been recently approved by the FDA to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those already exposed to the first-generation InSTI. Despite having a different mutational profile, some cross-resistance mutations may influence its susceptibility. The aim of this study was to evaluate the impact of a raltegravir-containing salvage regimen on dolutegravir activity. Patients and methods: Blood samples of 92 HIV-infected individuals with virological failure (two or more viral loads >50 copies/mL after 6 months of treatment) using raltegravir with optimized background therapy were sequenced and evaluated according to the Stanford University HIV Drug Resistance Database algorithm. Results: Among the 92 patients analysed, 32 (35%) showed resistance to dolutegravir, in most cases associated with the combination of Q148H/R/K with G140S/A mutations. At genotyping, patients with resistance to dolutegravir had viral load values closer to the highest previously documented viral load. Conclusions: Changes in viraemia during virological failure may indicate the evolution of raltegravir resistance and may predict the emergence of secondary mutations that are associated with a decrease in dolutegravir susceptibility. Early discontinuation of raltegravir from failing regimens might favour subsequent salvage with dolutegravir, but further studies are necessary to evaluate this issue. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Garcia J.A.,Institute Infectologia Emilio Ribas | Cimerman S.,Institute Infectologia Emilio Ribas
Revista da Sociedade Brasileira de Medicina Tropical | Year: 2012

Introduction: Studies strongly indicate Dientamoeba fragilis as one of the causes of diarrhea in human immunodeficiency virus (HIV) patients. Methods: The objective of the present study was to evaluate the prevalence of D. fragilis associated with the causes of diarrhea in 82 HIV/ AIDS patients hospitalized at the Instituto de Infectologia Emílio Ribas from September 2006 to November 2008. Results: In total, 105 samples were collected from 82 patients. Unprotected sex was the most frequent cause of HIV infection (46.3%), followed by the use of injectable or non-injectable drugs (14.6%). Patients presented with viral loads of 49-750,000 copies/ mL (average: 73,849 ± 124,850 copies/mL) and CD4 counts ranging of 2-1,306 cells/mm3 (average: 159 ± 250 cells/mm3). On an average, the odds of obtaining a positive result by using the other techniques (Hoffman, Pons and Janer or Lutz; Ritchie) were 2.7 times higher than the chance of obtaining a positive result by using the simplified iron hematoxylin method. Significant differences were found between the methods (p = 0.003). Conclusions: The other techniques can detect a significantly greater amount of parasites than the simplified iron hematoxylin method, especially with respect to Isospora belli, Cryptosporidium sp., Schistosoma mansoni, and Strongyloides stercoralis, which were not detected using hematoxylin. Endolimax nana and D. fragilis were detected more frequently on using hematoxylin, and the only parasite not found by the other methods was D. fragilis.


Goto H.,University of Sao Paulo | Lauletta Lindoso J.A.,University of Sao Paulo | Lauletta Lindoso J.A.,Institute Infectologia Emilio Ribas
Infectious Disease Clinics of North America | Year: 2012

Tegumentary leishmaniases are caused by approximately 15 species of protozoa of the genus Leishmania. They prevail in tropical and subtropical areas of the Old and New World but human mobility also makes them a medical problem in nonendemic areas. Clinical manifestations may comprise cutaneous and mucocutaneous forms that may be localized, disseminated, or diffuse in distribution and may differ in Old and New World leishmaniases. Diagnosis and treatment vary according to the clinical manifestations, geographic area, and Leishmania species involved. This article highlights the diversity and complexity of tegumentary leishmaniases, which are worsened by human immunodeficiency virus/. Leishmania coinfection. © 2012 Elsevier Inc.


Seguro A.C.,University of Sao Paulo | Andrade L.,University of Sao Paulo | Andrade L.,Institute Infectologia Emilio Ribas
Shock | Year: 2013

Leptospirosis is an acute septicemic illness that affects humans in all parts of the world. Approximately 10% of patients with leptospirosis develop severe disease, the Weil syndrome, with jaundice, acute kidney injury (AKI), and pulmonary hemorrhage. Leptospirosis-induced AKI is typically nonoliguric with a high frequency of hypokalemia. Experimental and clinical studies demonstrated that tubular function alterations precede a drop in the glomerular filtration rate and are mainly in the proximal tubule. Studies in humans and animals have demonstrated a decrease in the expression of proximal sodium (NHE3) and water tubular transporter, aquaporin 1 (AQP1) together with higher renal expression of the Na-K-2Cl cotransporter NKCC2. In an experimental model, at the initial phase of the disease, the expression of AQP2, the water transport of the collecting duct, is decreased, which explains the higher incidence of nonoliguric AKI. During the recovery phase of AKI, AQP2 expression increased in human and animals as a compensatory mechanism. Alveolar hemorrhage, pulmonary edema, acute respiratory distress syndrome, or a combination of these features may accompany AKI and is associated with high mortality. Studies with hamsters demonstrated that in leptospirosis a noncardiogenic pulmonary edema occurs consequently to a decrease in the clearance of alveolar fluid, due to a decrease in sodium transporter in the luminal membrane (ENaC) and an increase in the NKCC1 basolateral membrane transporter. Antibiotic treatment is efficient in the early and late/severe phases and revert all kidney transporters. Early and daily hemodialysis, low daily net fluid intake, and lung-protective strategies are recommended for critically ill patients with leptospirosis. Copyright © 2013 by the Shock Society.


Hazra R.,U.S. National Institutes of Health | Cohen R.A.,Westat | Gonin R.,Westat | Monteiro J.P.,University of Sao Paulo | And 3 more authors.
AIDS | Year: 2012

Background: Dyslipidemia is observed among older children and adults with HIV. We examined nonfasting cholesterol and triglycerides in two groups of 12-23-month-old Latin American children - HIV-infected vs. HIV-exposed but uninfected (HEU). Methods: HIV-infected and HEU children in Latin America and Jamaica were enrolled in an observational cohort. Eligibility for this analysis required having cholesterol and triglyceride results available during the second year of life. Results: HIV-infected (n=83) children were slightly older at the time of lipid testing than the HEU (n=681). Forty percent of the HIV-infected children were on protease inhibitor-based antiretroviral therapy (ART); 41% were not on ART. There was no statistically significant difference in mean cholesterol concentrations (mg/dl) by HIV status; however, the HIV-infected children had higher mean triglyceride concentrations. The prevalence of high cholesterol (>200 mg/dl) and high triglycerides (>110 mg/dl) was higher among the HIV-infected vs. HEU. Among the HIV-infected children, mean cholesterol and triglyceride concentrations varied by ART. Children receiving no ART had a significantly lower mean cholesterol concentration. Those receiving protease inhibitor-containing ART had a significantly higher mean triglyceride concentration compared to the other two antiretroviral regimen groups. Conclusion: A greater proportion of HIV-infected children at 12-23months have hyperlipidemia when compared to HEU children, with the highest triglyceride concentrations observed among those receiving protease inhibitor-containing ART, and the lowest cholesterol levels among those not receiving ART. Implications of these findings will require continued follow-up of HIV-infected children who initiate therapy early in life. © 2012 Lippincott Williams & Wilkins, Inc.


Strelow V.L.,Institute Infectologia Emilio Ribas | Vidal J.E.,Institute Infectologia Emilio Ribas
Arquivos de Neuro-Psiquiatria | Year: 2013

Invasive meningococcal disease (IMD) is a major public health and continues to cause substantial mortality and morbidity. Serotype C is the most frequent in Brazil. The clinical spectrum of IMD is broad (meningitis, meningococcemia or both) and the clinical evolution may be unpredictable. Main features associated with mortality are: age higher than 50 years old, seizures, shock, and meningococcemia without meningitis. Blood cultures should be obtained immediately. Lumbar puncture can be performed without previous computed tomography scan (CT) in most cases. Clinical features can be useful to predic patients where an abnormal CT scan is likely. Cerebrospinal fluid (CSF) culture and Gram stain should always be required. Latex agglutination sensitivity is highly variable. Polymerase chain reaction is specially useful when other methods are negative or delayed. Usually ceftriaxone should not be delayed while awaiting CSF study or CT. Dexamethasone can be used in meningococcal meningitis. Early suspicion of IMD and antibiotic in primary care before hospitalization, rapid transportation to a hospital, and stabilization in an intensive-care unit has substantially reduced the case-fatality rate. Vaccines against serotypes A, C, W-135, and Y are available while vaccines against serotype B are expected.


Alcaide M.L.,University of Miami | Parmigiani A.,University of Miami | Pallikkuth S.,University of Miami | Roach M.,University of Miami | And 5 more authors.
PLoS ONE | Year: 2013

Background: Persistent immune activation and microbial translocation associated with HIV infection likely place HIV-infected aging women at high risk of developing chronic age-related diseases. We investigated immune activation and microbial translocation in HIV-infected aging women in the post-menopausal ages. Methods: Twenty-seven post-menopausal women with HIV infection receiving antiretroviral treatment with documented viral suppression and 15 HIV-negative age-matched controls were enrolled. Levels of immune activation markers (T cell immune phenotype, sCD25, sCD14, sCD163), microbial translocation (LPS) and biomarkers of cardiovascular disease and impaired cognitive function (sVCAM-1, sICAM-1 and CXCL10) were evaluated. Results: T cell activation and exhaustion, monocyte/macrophage activation, and microbial translocation were significantly higher in HIV-infected women when compared to uninfected controls. Microbial translocation correlated with T cell and monocyte/macrophage activation. Biomarkers of cardiovascular disease and impaired cognition were elevated in women with HIV infection and correlated with immune activation. Conclusions: HIV-infected antiretroviral-treated aging women who achieved viral suppression are in a generalized status of immune activation and therefore are at an increased risk of age-associated end-organ diseases compared to uninfected age-matched controls. © 2013 Alcaide et al.


de Oliveira A.C.D.S.,Institute Infectologia Emilio Ribas | Focaccia R.,Institute Infectologia Emilio Ribas
Brazilian Journal of Infectious Diseases | Year: 2010

Bleeding due to the habit of removing the cuticles of the fi nger and toes nails, without appropriate sterilization of instruments can be an important factor of contamination by hepatitis B and C viruses. The objectives of this study were to verify the use of standards on biosafety in the routine work of manicurists and/or pedicurists located in São Paulo, Brazil; know the level of information they have about ways of transmission and prevention of hepatitis B and C; evaluate the degree of risk perception for accidental exposure to infectious agents; and to estimate the prevalence of serological markers of hepatitis B and C among them. This was descriptive, cross-sectional study that included a random sample of 100 manicurists and/or pedicurists working in beauty salons. We administered a questionnaire to obtain personal information about the characteristics of the participants, collected blood for hepatitis B and C serology and assessed the working environment. Adherence to the professional standards on biosafety has been inadequate, and we noted that only 5% used disposable gloves, none washed their hands, 93% did not previously cleaned their working material and only 7% used disposable materials. A low level of knowledge about the routes of transmission, prevention, standards of biosafety, and risk perception of the infectious agents in their professional activity was observed. One out of ten interviewed manicurist and/or pedicurist had serological markers of hepatitis B or C, with 8% of hepatitis B and 2% of hepatitis C. © sevier Editora Ltda.


Meira C.S.,University of Sao Paulo | Vidal J.E.,Institute Infectologia Emilio Ribas | Costa-Silva T.A.,University of Sao Paulo | Frazatti-Gallina N.,Instituto Butantan | Pereira-Chioccola V.L.,University of Sao Paulo
Diagnostic Microbiology and Infectious Disease | Year: 2011

Cerebral toxoplasmosis is the most common neurologic opportunistic infection in HIV-infected patients. Excretory-secretory antigens (ESA) are the majority of the circulating antigens in sera from hosts with acute toxoplasmosis, and their usefulness as antigens has been shown. This study considered whether it could find anti-ESA antibodies in cerebrospinal fluid (CSF) and whether these antibodies can be markers of active infection. Samples of CSF from 270 HIV-infected patients were analyzed and divided into 3 groups according to the presence or absence of active toxoplasmosis. Group I: 99 patients with cerebral toxoplasmosis; group II: 112 patients with other opportunistic neurologic diseases and seropositive for toxoplasmosis; and group III: 59 patients with other opportunistic neurologic diseases and seronegative for toxoplasmosis. Toxoplasma gondii ESA and a crude tachyzoite antigen were used as antigens using ELISA and immunoblotting. The statistical analysis was done using the F test and unpaired Student's t test. Crude tachyzoite antigen: mean ELISA-relative values ± standard error for CSF of groups I and II were 7.0 ± 0.27 and 3.9 ± 0.19, respectively. Variance analysis revealed that results of both groups of patients were statistically different (1.80, P = 0.0025). The difference between the mean results was 3.0 ± 0.3, and the Student's t test value was 9.41 (P = 0.0001). Samples from groups I and II were reactive by immunoblotting, with similar intensities. In ESA-ELISA, the mean for group I was 9.0 ± 0.39. Group II showed a mean value of 2.7 ± 0.12. Both groups were statistically different (9.16, P < 0.001). However, in ESA, the difference between the mean results was higher (6.2 ± 0.39) and the Student's t test value was 16.04 (P < 0.0001). Similar results were shown in immunoblotting where a CSF sample from group I reacted well with ESA, and the sample from a group II patient failed to do so. The mean ELISA-relative value of the control group (group III) was 0.5 ± 0.09 for the first antigen and 0.4 ± 0.22 for the second. ESA-ELISA and/or immunoblotting of CSF samples can be used for diagnosis of cerebral toxoplasmosis in association with clinical, serologic, and radiological information, thus providing a simple straightforward methodology, particularly suitable in countries with high prevalence of latent toxoplasmosis in the general population. © 2011 Elsevier Inc.

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