Browsing by Author "Zala, Carlos"
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Item Comparable Pharmacokinetics of Generic Indinavir (Inhibisam) Versus Brand Indinavir (Crixivan) When Boosted With Ritonavir(2005-03-01) Zala, Carlos; Alexander, Christopher; Ochoa, Claudia; Guillemi, Silvia; Ting, Lillian; Bonner, Simon; Cahn, Pedro; Harrigan, Richard P; Montaner, Julio SGLetter to editor about Comparable Pharmacokinetics of Generic Indinavir (Inhibisam) Versus Brand Indinavir (Crixivan) When Boosted With RitonavirItem Cytomegalovirus UL97 mutations associated with ganciclovir resistance in immunocompromised patients from Argentina(2004) Sánchez Puch, Santiago; Ochoa, Carlos; Carballal, Guillermo; Zala, Carlos; Cahn, Pedro; Brunet, Ricardo; Salomon, Horacio; Videla, CeciliaBackground: Prolonged therapy with ganciclovir (GCV) can result in the development of GCV-resistant strains due to mutations in the viral phosphotransferase (UL97 gene) and/or in the viral DNA polymerase (UL54 gene). Objectives: The purpose of this study was to detect by molecular methods the most prevalent UL97 mutants which confer ganciclovir-resistance in immunocompromised populations. Study design: Patients from two populations were selected: (a) renal transplant patients with active cytomegalovirus (CMV) infection and more than one cycle of GCV; (b) HIV-infected patients with retinitis due to CMV, who were under GCV induction, maintenance therapy or withdrawal. Patients were followed up by pp65 antigenemia and by viral isolation from blood or/and urine samples. Two fragments (133 and 255pb) of the UL97 gene were amplified by polymerase chain reaction (PCR) from CMV isolates. Results: Nine from 12 isolates obtained were sequenced, three from two renal transplant patients and six from five HIV-infected patients. A UL97 mutation, known to confer GCV resistance, was found in two isolates from a renal transplant patient. A methionine to valine mutation at codon 460 (M460V) was detected. These isolates exhibited another mutation at codon 605, whose amino acid changed from aspartic acid (D) to glutamic acid (E). These findings were observed after treatment with IV-GCV/ O-GCV/ IV-GCV for 151 days. The 605 mutation was also detected in leukocytes from the same patient previous to the beginning of the treatment with GCV. Conclusions: Although a known resistant mutation appeared in a renal transplant patient, it was not associated with CMV disease. We suggest that the D605E mutation could "partially or totally compensate" for the effect of GCV resistance conferred by the 460 mutation. Further studies should be performed to confirm this hypothesis.Item Determinants of Treatment Access in a Population-based Cohort of HIV-positive Men and Women Living in Argentina(2008-04-02) Zala, Carlos; Rustad, Clare A; Chan, Keith; Khan, Nabeela I; Beltran, Marcelo; Warley, Eduardo; Ceriotto, Mariana; Druyts, Eric F; Hogg, Robert S; Montaner, Julio; Cahn, Pedro; PUMA Study GroupObjective To report emerging data on the use of highly active antiretroviral therapy (HAART) in Argentina by assessing patterns of HAART access and late vs early treatment initiation in a population-based cohort of adults infected with HIV type-1. Design The Prospective Study on the Use and Monitoring of Antiretroviral Therapy (PUMA) is a study of 883 HIV-positive individuals enrolled in the Argentinean drug treatment program. Individuals were 16 years of age and older and were recruited from 10 clinics across Argentina. Methods Sociodemographic and clinical characteristics were examined using contingency tables (Pearson chi-square test and Fisher exact test) for categoric variables and Wilcoxon rank-sum test for continuous variables. To analyze time to initiation of HAART we used Kaplan-Meier methods and Cox regression. Results Patients who initiated HAART were more likely to be older, have an AIDS-defining illness, be an injection drug user (IDU), have a lower median CD4 cell count, have a higher median viral load, and be less likely to be men who have sex with men (MSM). In multivariate analysis, AIDS-defining illness and plasma viral load were significantly associated with time to starting therapy. Patients who received late access were more likely to be diagnosed with AIDS and have higher median plasma viral loads than those receiving early access. Conclusion Our results indicate that despite free availability of treatment, monitoring, and care in Argentina, a significant proportion of men and women are accessing HAART late in the course of HIV disease. Further characterization of the HIV-positive population will allow for a more comprehensive evaluation of the impact of HAART within the Argentinean drug treatment program.Item Higher Rate of Toxicity With No Increased Efficacy When Hydroxyurea Is Added to a Regimen of Stavudine Plus Didanosine and Nevirapine in Primary HIV Infection(2002-04-01) Zala, Carlos; Salomon, Horacio; Ochoa, Claudia; Kijak, Gustavo; Federico, Andrea; Perez, Héctor; Julio SG, Montaner; Cahn, PedroSummary: Twenty-four subjects presenting at a single treatment center with primary HIV infection were enrolled in a pilot study aimed to establish the possible role of hydroxyurea in this setting. Study participants were randomly assigned to receive or not to receive hydroxyurea in addition to stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP). Seventy-five percent of patients without hydroxyurea had plasma HIV RNA below 50 copies/mL at 48 weeks by both intention-to-treat (ITT) and on-treatment (OT) analysis in comparison with 50% (ITT) and 67% (OT) of patients with hydroxyurea (p > .1). A median increase of >200 cells/mm3 was observed from baseline to week 48 whether or not hydroxyurea was included in the regimen. Overall, in 12 patients treated with hydroxyurea, 33 adverse events were reported versus 19 reported for 12 patients who did not receive hydroxyurea (p < .05). Our results suggest that that adding hydroxyurea to a regimen of d4T plus ddI and NVP increases toxicity without improving the antiviral effect.Item Lack of viral selection in human immunodeficiency virus type 1 mother-to-child transmission with primary infection during late pregnancy and/or breastfeeding(2008) Ceballos, Ana; Andreani, Guadalupe; Ripamonti, Chiara; Dilernia, Dario; Mendez, Ramiro; Rabinovich, Roberto D.; Cardenas, Patricia; Zala, Carlos; Cahn, Pedro; Scarlatti, Gabriella; Martínez Peralta, LilianaMother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) as described for women with an established infection is, in most cases, associated with the transmission of few maternal variants. This study analysed virus variability in four cases of maternal primary infection occurring during pregnancy and/or breastfeeding. Estimated time of seroconversion was at 4 months of pregnancy for one woman (early seroconversion) and during the last months of pregnancy and/or breastfeeding for the remaining three (late seroconversion). The C2V3 envelope region was analysed in samples of mother-child pairs by molecular cloning and sequencing. Comparisons of nucleotide and amino acid sequences as well as phylogenetic analysis were performed. The results showed low variability in the virus population of both mother and child. Maximum-likelihood analysis showed that, in the early pregnancy seroconversion case, a minor viral variant with further evolution in the child was transmitted, which could indicate a selection event in MTCT or a stochastic event, whereas in the late seroconversion cases, the mother's and child's sequences were intermingled, which is compatible with the transmission of multiple viral variants from the mother's major population. These results could be explained by the less pronounced selective pressure exerted by the immune system in the early stages of the mother's infection, which could play a role in MTCT of HIV-1.Item Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure(2002-07-15) Kijak, Gustavo H; Simon, Viviana; Balfe, Peter; Vanderhoeven, Jeroen; Pampuro, Sandra E; Zala, Carlos; Ochoa, Claudia; Cahn, Pedro; Markowitz, Martin; Salomon, HoracioThe emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure. The different variants of human immunodeficiency virus type 1 (HIV-1) present in infected individuals have been described as quasispecies of related but distinct viruses; this plasticity of phenotype allows the virus to occupy a large adaptive landscape from which novel phenotypes may readily emerge (7, 17, 23). These variants are generated continuously due to the high replication rate of HIV-1 (50), the high frequency of recombination among viral genomes (4), and the lack of proofreading activity of the viral reverse transcriptase (RT) (41). When the selective pressure of antiretroviral (ARV) therapy is exerted on such a population, drug-resistant mutants may emerge and consequently lead to treatment failure (7, 37). The emergence of such viral variants has been extensively described and is found even in the setting of highly active ARV therapies (11, 39, 46). When this selective pressure is removed, the emergence of drug-sensitive quasispecies may be expected, as they would be predicted to have a higher fitness in a drug-free environment (9, 15, 19, 20, 22, 25, 34, 40, 42, 43). This rationale led to the many structured treatment interruption (STI) studies carried out on patients with treatment failure and multidrug-resistant viruses (10, 12, 16, 26, 45, 59). In those cohorts, a rise in plasma viral load and a concomitant fall in CD4+ cell count was observed after treatment interruption; in approximately half of the patients, drug susceptibility shifted from resistant to sensitive. However, the origin of these drug-sensitive quasispecies which emerged after STI has not been clearly defined. Understanding the mechanisms responsible for the observed changes in HIV-1 drug resistance and in viral replication after STI will provide a greater insight into HIV-1 evolution and will help define future therapeutic strategies for patients suffering treatment failure. The objective of this work was to determine the origin of drug-sensitive quasispecies arising after STI. New drug-sensitive HIV variants may be the result of point mutations (“back mutations”) in the drug-resistant quasispecies circulating immediately before STI, or they may be reemerging ancestral viral variants that had circulated before the drug-resistant viruses associated with treatment failure arose (and which had been sequestrated or suppressed during therapy). In addition we assessed whether the increase in viral load and decrease in CD4+ cell count observed after STI was associated with a change in the biological phenotype of the virus from non-syncytium-inducing/CCR5-tropic to syncytium-inducing/CXCR4-tropic. Like STI, this latter phenotype has been associated with faster replication, more rapid decline in CD4 numbers, and disease progression (6, 8, 21, 28, 56). We were able to show that viral quasispecies replicating after treatment interruption were not related to its immediate temporal ancestor but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen. (The present study constitutes a part of Gustavo H. Kijak's doctoral work at the University of Buenos Aires.)Item Randomized, Controlled Study of the Effects of a Short Course of Prednisone on the Incidence of Rash Associated With Nevirapine in Patients Infected With HIV-1(2003-05-01) Montaner, Julio S.G; Cahn, Pedro; Zala, Carlos; Casssetti, Lidia; Losso, Marcelo; Hall, David B; Wruck, Jan; McDonough, Marita; Gigliotti, Maria; Robinson, Patrick A; The 1100.1286 Study TeamObjective: To examine the effect of 2 weeks of treatment with prednisone on the incidence of nevirapine-associated rash in HIV-1-infected patients receiving combination antiretroviral therapy. Methods: This was a 24-week, prospective, randomized, open-label, international study. Patients were randomized to receive nevirapine plus open-label prednisone (40 mg once daily for 14 days) (n = 69) or nevirapine alone (n = 69). All patients received at least two other antiretroviral drugs. Nevirapine was administered at the lead-in dosage of 200 mg once daily. After the initial 2 weeks of the study, the nevirapine dosage was increased to 200 mg twice daily. Results: During the first 6 weeks of treatment, rash was not reduced in the patients who received prednisone: prednisone treatment group, 23 (33%)/69; nonprednisone treatment group, 13 (19%)/69 (one-tailed Fisher exact test for prednisone reducing the incidence of rash, p = .984). There tended to be more severe rashes (7% versus 1%, respectively) and more therapy discontinuations due to rash (16% versus 9%, respectively) in the prednisone treatment group than in the nonprednisone treatment group. Risk factors for rash included higher pretreatment CD4 cell count, lower HIV-1 RNA level, female sex, and higher trough nevirapine concentrations. The prednisone treatment group had a marked increase in the median CD4 cell count in the first 2 weeks, which stabilized at a level similar to that in the nonprednisone treatment group. HIV-1 RNA responses were similar between the two groups. Treatment-naive patients had similar decreases in plasma HIV-1 RNA levels at week 24: approximately 2.3 log10 copies/mL. Conclusions: This study demonstrated that 2 weeks of concomitant therapy with prednisone does not decrease the occurrence of nevirapine-associated rash. The use of prednisone is not recommended to prevent rash in patients receiving nevirapine. Prednisone administration had no adverse effects on the virological responses or on CD4 cell count changes at 24 weeks.Item 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, PedroObjective: 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.Item Venous and Arterial Blood Lactate in HIV-Infected Patients(2002-12) Zala, Carlos; Harris, Marianne; Ochoa, Claudia; Tocci, Mariel; Quercia, Romina; Mittelman, Graciela; Graciela, Héctor; Cahn, Pedro; Montaner, Julio SGHyperlactataemia is increasingly recognised as a complication of nucleoside analogue-based antiretroviral therapy [1–5]. There is, however, some debate about the accuracy of peripheral venous blood lactate levels and whether these adequately reflect arterial lactate levels. This correlation has been demonstrated in the non-HIV, emergency medicine literature [6,7], but has not been studied in HIV patients receiving antiretroviral therapy. Therefore, we undertook the present study to compare venous versus arterial lactate levels in HIV patients who had consistently high random venous lactate while receiving chronic stavudine-based antiretroviral therapy.