DSpace Repository :: Browsing by Author "Krolewiecki, Alejandro J."

Browsing by Author "Krolewiecki, Alejandro J."

Now showing 1 - 11 of 11

A phase 4, single-arm, open-label, pilot study of maraviroc, raltegravir and darunavir/r in HIV-1 adults with triple class failure: TERCETO study
(2012) Patterson, Patricia; Magneres, Claudia; Sued, Omar; Fink, Valeria; Figueroa, Maria Ines; Cesar, Carina; Gun, Ana; Cahn, Pedro; Krolewiecki, Alejandro J.
The purpose of this phase 4, single-arm, open-label study was to evaluate the safety, tolerability, efficacy, antiviral and immunological activity of maraviroc (MVC) in combination with raltegravir (RGV) and darunavir/r (DRV/r) in adult HIV-1 infected patients (pts) with limited treatment options. HIV-1 pts with documented virologic triple class failure or multi-drug class resistance defined as the presence of Q151 complex, 69 insertion complex and/or≥3 TAMs for NRTIs and K103N, G190S+Y181C or Y188L mutants for NNRTIs and≥3 RAMs (L10F/I/R/V; M46I/L; I54V/M/L; V82A/F/T/S; I84V; L90M) for protease inhibitors (PIs) were offered a triple drug regimen consisting of MVC 150 mg BID, RGV 400 mg BID and DRV/r 600/100 mg BID. Safety, lipid profile and virologic efficacy were evaluated at week 4, 12, 24, 36 and 48. Between January 2010 and March 2012, 27 pts were enrolled. Screening failure rate was 52% due to undetectable viral load (pVL) or non R5 tropism type (Trofile™). Despite being heavily pre-treated pts, only 26% had negative tropism test at SCR. Baseline characteristics of 13 included pts were: 77% male, median age 43 years (IQR: 40.1–48.6), 38% had a prior AIDS-defining condition. Median BSL pVL was 23,350 cps/mL (4.4 log10) (IQR: 11,236–55,785) and median CD4 was 222 cells/mm3 (IQR: 179–318). Median time on NRTIs, NNRTIs and PIs were 10.7 (8.6–13.7), 1.7 (1.3–7.6) and 5.4 (4.7–10) years respectively. Pts had received a median of 2 PIs (IQR: 2–3). 8/13 pts showed thymidine analogue-associated mutations (TAMs), and≥2 were present in 5/13. Detectable NNRTI resistance-associated mutations (RAMs) were present in 10/13 patients. 9/13 had≥4 primary PI RAMs. At 48 weeks, 2 pts had discontinued therapy (OIs related death (cryptococcal meningitis)=1, withdrawn from the study on W36 due to blips despite not achieving criteria for virologic failure=1) and the remaining pts (11/13) achieved undetectable pVL and increased CD4 in 133 cell/mm3 from BSL (IQR: 81–174.5). Median total cholesterol levels increased from 162 mg/dL (IQR: 135-188) to 215 mg/dL (IQR: 182–237) between BSL/W48; median change in cholesterol levels: 40 mg/dL (IQR: 6.5-66). Salvage therapy including MVC, RGV and DRV/r achieved sustained reductions in pVL (<50 copies/mL) through 48 weeks of therapy in this pilot study with no treatment limiting toxicity.
Acute retroviral syndrome and high baseline viral load are predictors of rapid HIV progression among untreated Argentinean seroconverters
(2011) Socias, Maria E.; Sued, Omar; Laufer, Natalia; Lázaro, Maria E.; Mingrone, Hugo; Remondegui, Claudio; Figueroa, Maria Ines; Cesar, Carina; Gun, Ana; Turk, Gabriela; Bouzas, Maria B.; Kavasery, Rosanna; Krolewiecki, Alejandro J.; Perez, Hector; Salomon, Horacio; Pryluka, Damian
Background Diagnosis of primary HIV infection (PHI) has important clinical and public health implications. HAART initiation at this stage remains controversial. Methods Our objective was to identify predictors of disease progression among Argentinean seroconverters during the first year of infection, within a multicentre registry of PHI-patients diagnosed between 1997 and 2008. Cox regression was used to analyze predictors of progression (LT-CD4 < 350 cells/mm3, B, C events or death) at 12 months among untreated patients. Results Among 134 subjects, 74% presented with acute retroviral syndrome (ARS). Seven opportunistic infections (one death), nine B events, and 10 non-AIDS defining serious events were observed. Among the 92 untreated patients, 24 (26%) progressed at 12 months versus three (7%) in the treated group (p = 0.01). The 12-month progression rate among untreated patients with ARS was 34% (95% CI 22.5-46.3) versus 13% (95% CI 1.1-24.7) in asymptomatic patients (p = 0.04). In univariate analysis, ARS, baseline LT-CD4 < 350 cells/mm3, and baseline and six-month viral load (VL) > 100,000 copies/mL were associated with progression. In multivariate analysis, only ARS and baseline VL > 100,000 copies/mL remained independently associated; HR: 8.44 (95% CI 0.97-73.42) and 9.44 (95% CI 1.38-64.68), respectively. Conclusions In Argentina, PHI is associated with significant morbidity. HAART should be considered in PHI patients with ARS and high baseline VL to prevent disease progression.
Cancer in HIV-Infected Persons From the Caribbean, Central and South America
(2011) Fink, Valeria; Shepherd, Bryan E.; Cesar, Carina; Krolewiecki, Alejandro J.; Wehbe, Francisco; Cortes, Claudia; Crabtree-Ramirez, Brenda; Padgett, Denis; Shafaee, Mehdi; Schechter, Mauro; Gotuzzo, Eduardo; Bacon, Melanie; McGowan, Catherine C.; Cahn, Pedro; Masys, Daniel R.; Caribbean Central South America Network for HIV Research Collaboration of the International Epidemiologic Databases to Evaluate AIDS Program
Background: HIV-infected individuals have heightened cancer risk. With the advent of highly active antiretroviral therapy (HAART), the frequency of some AIDS-defining cancers (ADC) has decreased although certain non-AIDS-defining cancers (NADC) are becoming more frequent. Cancers among HIV-infected individuals in Latin American and the Caribbean have not yet been carefully studied. Methods: Cancer cases among the Caribbean, Central and South American network for HIV Research (CCASAnet) cohort were identified reviewing clinical records and pre-existing databases. Results: There were 406 cancers reported: 331 ADC (224 Kaposi sarcomas and 98 non Hodgkin lymphomas). Most frequent NADC (n = 75) were Hodgkin lymphoma and skin cancers. Seventy-three percent of NADC and 45% of ADC were diagnosed >1 year after HIV diagnosis. Fifty-six percent of ADC occurred before HAART start. Median time from HAART start until cancer diagnosis was 2.5 years for NADC and 0.5 years for ADC (P = <0.001). Within 3372 HAART starters, 158 were diagnosed with 165 cancers (82.4% ADC); 85 cases were previous to or concomitant with HAART initiation. Incidence of cancer after HAART initiation in 8080 person-years of follow-up was 7.2 per 1000 person-years (95% confidence interval = 5.5 to 9.3) for ADC and 2.7 (95% confidence interval = 1.8 to 4.1) for NADC; incidence was higher in the first 2 months, particularly for ADC (47.6). A pre-HAART ADC was a predictor of mortality after adjusting for age, sex, and CD4 at HAART initiation. Conclusions: ADC were the most frequent cancers in this region and were often diagnosed close to HIV diagnosis and HAART start. Incidence of cancer was highest around HAART initiation.
Improved diagnosis of Strongyloides stercoralis using recombinant antigen-based serologies in a community-wide study in northern Argentina
(2010) Krolewiecki, Alejandro J.; Ramanathan, Roshan; Fink, Valeria; McAuliffe, Isabel; Cajal, Silvana P.; Won, Kimberly; Juarez, Marisa; Di Paolo, Adriana; Tapia, Laura; Acosta, Norma; Lee, Rogan; Lammie, Patrick; Abraham, David; Nutman, Thomas B.
The serodiagnosis of Strongyloides stercoralis infection by enzyme-linked immunosorbent assays based on crude antigen (CrAg-ELISA), while useful, has been limited by the reliance on crude parasite extracts. Newer techniques such as the luciferase immunoprecipitation system assay (LIPS), based on a 31-kDa recombinant antigen (termed NIE) from S. stercoralis and/or the recombinant antigen S. stercoralis immunoreactive antigen (SsIR), or the NIE-ELISA have shown promise in controlled settings. We compared each of these serologic assays in individuals from both regions of the world in which S. stercoralis is endemic and those in which it is not. A comprehensive stool evaluation (sedimentation concentration, Baermann concentration with charcoal cultures, agar plate, and Harada-Mori) and four different serologic techniques using CrAg-ELISA or recombinant NIE-ELISA as well as LIPS using NIE alone or in combination with a second recombinant antigen (NIE/SsIR-LIPS) were compared among individuals with parasitologically proven infection (n = 251) and healthy controls from regions of the world in which the infection is nonendemic (n = 11). Accuracy was calculated for each assay. The prevalence of S. stercoralis infection was 29.4% among Argentinean stool samples (n = 228). Sedimentation concentration and Baermann were the most sensitive stool-based methods. NIE-LIPS showed the highest sensitivity (97.8%) and specificity (100%) of the serologic assays. The calculated negative predictive value was highest for both the NIE-LIPS and CrAg-ELISA (>97%) irrespective of disease prevalence. No cross-reactivity with soil-transmitted helminths was noted. NIE-LIPS compares favorably against the current CrAg-ELISA and stool evaluation, providing additional accuracy and ease of performance in the serodiagnosis of S. stercoralis infections irrespective of disease prevalence.
La importancia del diagnóstico temprano en la supervivencia de los pacientes HIV positivos
(2010) Dilernia, Dario; Monaco, Carolina; Krolewiecki, Alejandro J.; Cesar, Carina; Cahn, Pedro; Salomon, Horacio
En la Argentina, el diagnóstico del HIV se realiza por solicitud voluntaria de los individuos o a través de la detección de sintomatología asociada a la infección. Sin embargo, debido a la elevada proporción de sujetos portadores que desconocen su estado serológico son necesarias nuevas estrategias. En el presente artículo mostramos cómo un modelo matemático predice el impacto de la expansión de la prueba diagnóstica del HIV en la Argentina. El modelo se basa en matrices de Markov y utiliza probabilidades de transición dependientes de parámetros obtenidos de estudios de cohortes nacionales e internacionales. Las predicciones incluyen tiempo en estadios clínicos y tratamiento, conteo de CD4, carga viral, estadío de infección, edad, tasas de mortalidad y proporción de infección desconocida a nivel poblacional. Las simulaciones se desarrollaron para la situación actual y para un escenario hipotético con diagnóstico más temprano. Mostramos predicciones que sugieren que el diagnóstico realizado antes de la progresión a sida incrementaría la expectativa de vida en unos 10.7 años. También, mostramos cómo la reducción del tiempo al diagnóstico hasta 5 años o menos desde la infección reduciría la tasa de mortalidad en el primer año de HAART de 7.6% a 2.1%, la proporción de infección no reconocida de 43.2% a 23.8% y la proporción de individuos con infección desconocida y que requieren tratamiento de 12% a 0.2%. Basados en estas predicciones resaltamos la importancia de implementar políticas de salud destinadas a detectar la infección por HIV en estadios tempranos en la Argentina.
Mortality During the First Year of Potent Antiretroviral Therapy in HIV-1-Infected Patients in 7 Sites Throughout Latin America and the Caribbean
(2009) Tuboi, Suely H.; Schechter, Mauro; McGowan, Catherine C.; Cesar, Carina; Krolewiecki, Alejandro J.; Cahn, Pedro; Wolff, Marcelo; Pape, Jean W.; Padgett, Denis; Sierra Madero, Juan; Gotuzzo, Eduardo; Masys, Daniel R.; Shepherd, Bryan E.
Background: Although nearly 2 million people live with HIV in Latin America and the Caribbean, mortality rates after initiation of highly active antiretroviral therapy (HAART) have not been well described. Methods: Five thousand one hundred fifty-two HIV-infected, antiretroviral-naive adults from clinics in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru starting HAART during 1996-2007 were included. First-year mortality rates and their association with demographics, regimen, baseline CD4, and clinical stage were assessed. Results: Overall 1-year mortality rate was 8.3% [95% confidence interval (CI): 7.6% to 9.1%], although variable across sites: 2.6%, 3.7%, 6.0%, 13.0%, 10.8%, 3.5%, and 9.8% for clinics in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru, respectively. Eighty percent of deaths occurred within the first 6 months. Median baseline CD4 was 107 cells per milliliter, ranging from 79 (Peru) to 163 (Argentina). Mortality estimates adjusting for CD4 were similar across sites (1.1%-2.8% for CD4 = 200), except for Haiti, 7.5%, and Honduras, 7.0%. Death was associated with lower CD4 [adjusted hazard ratio for CD4 = 200 vs. CD4 = 50 was 0.58; 95% CI: 0.40 to 0.85] and clinical AIDS (hazard ratio = 3.1; 95% CI: 2.1 to 4.5). Conclusions: Mortality rates were similar to those reported elsewhere for resource-limited settings. Disease stage at HAART initiation, treatment eligibility criteria, program age, and background mortality rates may explain some variability in prognosis between sites.
Pilot, Randomized Study Assessing Safety, Tolerability and Efficacy of Simplified LPV/r Maintenance Therapy in HIV Patients on the 1 PI-Based Regimen
(2011) Cahn, Pedro; Montaner, Julio; Junod, Patrice; Patterson, Patricia; Krolewiecki, Alejandro J.; Andrade-Villanueva, Jaime; Cassetti, Isabel; Sierra Madero, Juan; Casiro, A. D.; Bortolozzi, Raul; Lupo, Silvana H.; Longo, Nancy; Rampakakis, Emmanouil; Ackad, Nadia; Sampalis, John S.
Objectives To compare the efficacy and safety of an individualized treatment-simplification strategy consisting of switching from a highly-active anti-retroviral treatment (HAART) with a ritonavir-boosted protease inhibitor (PI/r) and 2 nucleoside reverse-transcriptase inhibitors (NRTIs) to lopinavir/ritonavir (LPV/r) monotherapy, with intensification by 2 NRTIs if necessary, to that of continuing their HAART. Methods This is a one-year, randomized, open-label, multi-center study in virologically-suppressed HIV-1-infected adults on their first PI/r-containing treatment, randomized to either LPV/r-monotherapy or continue their current treatment. Treatment efficacy was determined by plasma HIV-1 RNA viral load (VL), time-to-virologic rebound, patient-reported outcomes (PROs) and CD4+T-cell-count changes. Safety was assessed with the incidence of treatment-emergent adverse events (AE). Results Forty-one patients were randomized to LPV/r and 39 to continue their HAART. No statistically-significant differences between the two study groups in demographics and baseline characteristics were observed. At day-360, 71(39:LPV/r;32:HAART) patients completed treatment, while 9(2:LPV/r;7:HAART) discontinued. In a Last Observation Carried Forward Intent-to-Treat analysis, 40(98%) patients on LPV/r and 37(95%) on HAART had VL<200copies/mL (P = 0.61). Time-to-virologic rebound, changes in PROs, CD4+ T-cell-count and VL from baseline, also exhibited no statistically-significant between-group differences. Most frequent AEs were diarrhea (19%), headache (18%) and influenza (16%). Four (10%) patients on LPV/r were intensified with 2 NRTIs, all regaining virologic control. Eight serious AEs were reported by 5(2:LPV/r;3:HAART) patients. Conclusion At day-360, virologic efficacy and safety of LPV/r appears comparable to that of a PI+2NRTIs HAART. These results suggest that our individualized, simplified maintenance strategy with LPV/r-monotherapy and protocol-mandated NRTI re-introduction upon viral rebound, in virologically-suppressed patients merits further prospective long-term evaluation.
Prioritizing CD4 Count Monitoring in Response to ART in Resource-Constrained Settings: A Retrospective Application of Prediction-Based Classification
(2012) Azzoni, Livio; Foulkes, Andrea S.; Liu, Yan; Li, Xin; Johnson, Mark; Smith, Charles; Kamarulzaman, Adeeba; Montaner, Julio; Mounzer, Joseph; Saag, Michael; Cahn, Pedro; Cesar, Carina; Krolewiecki, Alejandro J.; Sanne, Ian; Montaner, Luis J.
Background Global programs of anti-HIV treatment depend on sustained laboratory capacity to assess treatment initiation thresholds and treatment response over time. Currently, there is no valid alternative to CD4 count testing for monitoring immunologic responses to treatment, but laboratory cost and capacity limit access to CD4 testing in resource-constrained settings. Thus, methods to prioritize patients for CD4 count testing could improve treatment monitoring by optimizing resource allocation. Methods and Findings Using a prospective cohort of HIV-infected patients (n=1,956) monitored upon antiretroviral therapy initiation in seven clinical sites with distinct geographical and socio-economic settings, we retrospectively apply a novel prediction-based classification (PBC) modeling method. The model uses repeatedly measured biomarkers (white blood cell count and lymphocyte percent) to predict CD4+ T cell outcome through first-stage modeling and subsequent classification based on clinically relevant thresholds (CD4+ T cell count of 200 or 350 cells/µl). The algorithm correctly classified 90% (cross-validation estimate=91.5%, standard deviation [SD]=4.5%) of CD4 count measurements <200 cells/µl in the first year of follow-up; if laboratory testing is applied only to patients predicted to be below the 200-cells/µl threshold, we estimate a potential savings of 54.3% (SD=4.2%) in CD4 testing capacity. A capacity savings of 34% (SD=3.9%) is predicted using a CD4 threshold of 350 cells/µl. Similar results were obtained over the 3 y of follow-up available (n=619). Limitations include a need for future economic healthcare outcome analysis, a need for assessment of extensibility beyond the 3-y observation time, and the need to assign a false positive threshold. Conclusions Our results support the use of PBC modeling as a triage point at the laboratory, lessening the need for laboratory-based CD4+ T cell count testing; implementation of this tool could help optimize the use of laboratory resources, directing CD4 testing towards higher-risk patients. However, further prospective studies and economic analyses are needed to demonstrate that the PBC model can be effectively applied in clinical settings.
Rates and Reasons for Early Change of First HAART in HIV-1-Infected Patients in 7 Sites throughout the Caribbean and Latin America
(2010) Cesar, Carina; Shepherd, Bryan E.; Krolewiecki, Alejandro J.; Fink, Valeria; Schechter, Mauro; Tuboi, Suely H.; Wolff, Marcelo; Pape, Jean W.; Leger, Paul; Padgett, Denis; Sierra Madero, Juan; Gotuzzo, Eduardo; Sued, Omar; McGowan, Catherine C.; Masys, Daniel R.; Cahn, Pedro; Caribbean, Central and South America Network for HIV Research (CCASAnet) Collaboration; International Epidemiologic Databases to Evaluate AIDS (IeDEA) Program
Background: HAART rollout in Latin America and the Caribbean has increased from approximately 210,000 in 2003 to 390,000 patients in 2007, covering 62% (51%-70%) of eligible patients, with considerable variation among countries. No multi-cohort study has examined rates of and reasons for change of initial HAART in this region. Methodology: Antiretroviral-naïve patients >or= 18 years who started HAART between 1996 and 2007 and had at least one follow-up visit from sites in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru were included. Time from HAART initiation to change (stopping or switching any antiretrovirals) was estimated using Kaplan-Meier techniques. Cox proportional hazards modeled the associations between change and demographics, initial regimen, baseline CD4 count, and clinical stage. Principal findings: Of 5026 HIV-infected patients, 35% were female, median age at HAART initiation was 37 years (interquartile range [IQR], 31-44), and median CD4 count was 105 cells/uL (IQR, 38-200). Estimated probabilities of changing within 3 months and one year of HAART initiation were 16% (95% confidence interval (CI) 15-17%) and 28% (95% CI 27-29%), respectively. Efavirenz-based regimens and no clinical AIDS at HAART initiation were associated with lower risk of change (hazard ratio (HR) = 1.7 (95% CI 1.1-2.6) and 2.1 (95% CI 1.7-2.5) comparing neverapine-based regimens and other regimens to efavirenz, respectively; HR = 1.3 (95% CI 1.1-1.5) for clinical AIDS at HAART initiation). The primary reason for change among HAART initiators were adverse events (14%), death (5.7%) and failure (1.3%) with specific toxicities varying among sites. After change, most patients remained in first line regimens. Conclusions: Adverse events were the leading cause for changing initial HAART. Predictors for change due to any reason were AIDS at baseline and the use of a non-efavirenz containing regimen. Differences between participant sites were observed and require further investigation.
Safe Treatment Interruptions in Patients With Nadir CD4 Counts of More Than 350 Cells/μL
(2006-04-01) Krolewiecki, Alejandro J.; Zala, Carlos; Vanzulli, Claudia; Pérez, Héctor; Iannella, María del Carmen; Bouzas, María Belén; Gun, Ana; Valiente, José; Cassetti, Isabel; Cahn, Pedro
Objective: To evaluate clinical, immunologic, and virologic performance of patients with nadir CD4 counts of >350cells/μL upon treatment interruption. Design: Randomized, open-label clinical trial of 48 weeks' duration. Methods: Patients on effective highly active antiretroviral therapy, with nadir CD4 counts of >350 cells/μL and peak viral loads of <50,000 copies/mL were randomized to continue therapy or to interrupt antiretroviral medication. End points for patients with treatment interruption were CD4 counts of <350 cells/μL, viral loads of >1 log above the pretherapy values, or clinical symptoms attributable to HIV, at which point treatment was restarted. In the continuation group, the end points were virologic failure, opportunistic infections, and treatment discontinuation due to toxicities. Results: Twenty patients were randomized to stop therapy and 16 patients to continue. Median CD4 counts at baseline were 643 cells/μL for the interruption group and 633 cells/μL for the continuation group. No end points were reached in the interruption group. By week 8, viral load returned to values comparable to those of pretherapy in all patients in the interruption group and remained stable until week 48. CD4 counts dropped in the interruption group (median loss of 156 cells/μL) at week 48. Significant decreases in venous lactate were observed in the interruption group. Conclusions: Treatment interruptions in patients with nadir CD4 counts of >350 cells/μL seem safe for at least 48 weeks. Pretherapy viral load appears as a valuable tool to predict its level at week 48.
Use of darunavir and enfuvirtide in a pregnant woman
(2009) Sued, Omar; Lattner, Julia; Gun, Ana; Patterson, Patricia; Abusamra, Lorena; Cesar, Carina; Fink, Valeria; Krolewiecki, Alejandro J.; Cahn, Pedro
A 41-year-old pregnant woman with multiple virological failures started darunavir, enfuvirtide, zidovudine and lamivudine at week 28 of pregnancy. During week 38, the patient had a viral load <400 copies/mL and a CD4 count of 180 cells/mm(3) (13%). The child was found to be in good health, with negative HIV-polymerase chain reactions at birth, at two and at six months.

Browsing by Author "Krolewiecki, Alejandro J."

Results Per Page

Sort Options