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Dive into the research topics where Zehava Grossman is active.

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Featured researches published by Zehava Grossman.


The Journal of Infectious Diseases | 2005

Prevalence of Drug-Resistant HIV-1 Variants in Untreated Individuals in Europe: Implications for Clinical Management

Annemarie M. J. Wensing; David A. M. C. van de Vijver; Gioacchino Angarano; Birgitta Åsjö; Claudia Balotta; Enzo Boeri; Ricardo Jorge Camacho; Maire-Laure Chaix; Dominique Costagliola; Andrea De Luca; Inge Derdelinckx; Zehava Grossman; Osamah Hamouda; Angelos Hatzakis; Robert Hemmer; Andy I. M. Hoepelman; Andrzej Horban; Klaus Korn; Claudia Kücherer; Thomas Leitner; Clive Loveday; E MacRae; I Maljkovic; Carmen de Mendoza; Laurence Meyer; Claus Nielsen; Eline Op de Coul; Vidar Ormaasen; D Paraskevis; Luc Perrin

BACKGROUND Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) can impair the response to combination therapy. Widespread transmission of drug-resistant variants has the disturbing potential of limiting future therapy options and affecting the efficacy of postexposure prophylaxis. METHODS We determined the baseline rate of drug resistance in 2208 therapy-naive patients recently and chronically infected with HIV-1 from 19 European countries during 1996-2002. RESULTS In Europe, 1 of 10 antiretroviral-naive patients carried viruses with > or = 1 drug-resistance mutation. Recently infected patients harbored resistant variants more often than did chronically infected patients (13.5% vs. 8.7%; P=.006). Non-B viruses (30%) less frequently carried resistance mutations than did subtype B viruses (4.8% vs. 12.9%; P<.01). Baseline resistance increased over time in newly diagnosed cases of non-B infection: from 2.0% (1/49) in 1996-1998 to 8.2% (16/194) in 2000-2001. CONCLUSIONS Drug-resistant variants are frequently present in both recently and chronically infected therapy-naive patients. Drug-resistant variants are most commonly seen in patients infected with subtype B virus, probably because of longer exposure of these viruses to drugs. However, an increase in baseline resistance in non-B viruses is observed. These data argue for testing all drug-naive patients and are of relevance when guidelines for management of postexposure prophylaxis and first-line therapy are updated.


The Journal of Infectious Diseases | 2009

Transmission of Drug-Resistant HIV-1 Is Stabilizing in Europe

Jurgen Vercauteren; Annemarie M. J. Wensing; David A. M. C. van de Vijver; Jan Albert; Claudia Balotta; Osamah Hamouda; Claudia Kücherer; Daniel Struck; Jean-Claude Schmit; Birgitta Åsjö; Marie Bruckova; Ricardo Jorge Camacho; Bonaventura Clotet; Suzie Coughlan; Zehava Grossman; Andrzej Horban; Klaus Korn; Leondios G. Kostrikis; Claus Nielsen; Dimitrios Paraskevis; Mario Poljak; Elisabeth Puchhammer-Stöckl; Chiara Riva; Lidia Ruiz; Mika Salminen; Rob Schuurman; Anders Sönnerborg; Danica Stanekova; Maja Stanojevic; Anne-Mieke Vandamme

The SPREAD Programme investigated prospectively the time trend from September 2002 through December 2005 of transmitted drug resistance (TDR) among 2793 patients in 20 European countries and in Israel with newly diagnosed human immunodeficiency virus type 1 (HIV-1) infection. The overall prevalence of TDR was 8.4% (225 of 2687 patients; 95% confidence interval [CI], 7.4%-9.5%), the prevalence of nucleoside reverse-transcriptase inhibitor (NRTI) resistance was 4.7% (125 of 2687 patients; 95% CI, 3.9%-5.5%), the prevalence of nonucleoside reverse-transcriptase inhibitor (NNRTI) resistance was 2.3% (62 of 2687 patients; 95% CI, 1.8%-2.9%), and the prevalence of protease inhibitor (PI) resistance was 2.9% (79 of 2687 patients; 95% CI, 2.4%-3.6%). There was no time trend in the overall TDR or in NRTI resistance, but there was a statistically significant decrease in PI resistance (P = .04) and in NNRTI resistance after an initial increase (P = .02). We found that TDR appears to be stabilizing in Europe, consistent with recent reports of decreasing drug resistance and improved viral suppression in patients treated for HIV-1 infection.


Nature Medicine | 1999

Ongoing HIV dissemination during HAART

Zvi Grossman; Michael A. Polis; Mark B. Feinberg; Zehava Grossman; Itschak Levi; Shirley Jankelevich; Robert Yarchoan; Jacob Boon; Frank de Wolf; Joep M. A. Lange; Jaap Goudsmit; Dimiter S. Dimitrov; William E. Paul

Multiphasic HIV decrease in individuals treated with anti-retroviral drugs has been modeled as the independent decay, with different half-lives, of distinct pools of cells infected before the initiation of treatment. We analyzed the kinetics of plasma HIV RNA in individuals receiving combinations of up to five drugs. The initial rates of decline increased substantially with the efficacy of treatment. Decline rates decreased with time, approaching zero in some cases. These observations are better explained if most of the virus is produced by cells infected after the initiation of therapy. Accordingly, treatment results in ongoing HIV infection cycles of decreasing amplitude, but the decrease progressively attenuates and may cease altogether at some viral load. We propose that HIV replication occurs in multiple local bursts, associated with immune activation in response to antigens. Current anti-retroviral drugs substantially reduce the size of these bursts and diminish their frequency but fail to abolish them.


Antimicrobial Agents and Chemotherapy | 2004

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Zehava Grossman; Ellen E. Paxinos; Diana Averbuch; Shlomo Maayan; Neil T. Parkin; Dan Engelhard; Margalit Lorber; Valery Istomin; Yael Shaked; Ella Mendelson; Daniela Ram; Chris Petropoulos; Jonathan M. Schapiro

ABSTRACT Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as “subtype-C-infected patients”) versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC50) change in susceptibility to nelfinavir only. Other mutations increased IC50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ± 22% to 22% ± 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.


AIDS | 2004

Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C.

Zehava Grossman; Valery Istomin; Diana Averbuch; Margalit Lorber; Klaris Risenberg; Itzchak Levi; Michal Chowers; Michael Burke; Nimrod Bar Yaacov; Jonathan M. Schapiro

Objective: Genetic differences between subtypes of HIV-1, even when not associated with key resistance mutations, are known to affect baseline susceptibility to specific antiretroviral drugs and resistance-development pathways. We studied the prevalence and patterns of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations in HIV-1 subtype C-infected patients. Method: We analysed the genetic variation at sites associated with NNRTI and nucleoside reverse transcriptase inhibitor resistance in subtype C- versus B-infected patients, both drug-naive and -experienced. We extended the comparison to subtype B records from the Stanford database. Results: A total of 150 subtype B and 341 subtype C-infected patients were studied. No significant differences were found in treatment and clinical parameters between the groups. In NNRTI-naive patients, changes in NNRTI positions were present in 9.3% of subtype B- versus 33.1% of subtype C-infected patients (P < 0.001). Differences were seen in both drug-naive (subtype B, 10.0% versus subtype C, 50.1%; P < 0.021) and drug-experienced NNRTI-naive patients (subtype B, 9.0% versus subtype C, 23.8%; P < 0.001). In NNRTI experienced patients, the number of A98G/S changes was significantly higher in subtype C patients treated with either efavirenz or nevirapine (P < 0.0001), and V106M was higher in efavirenz-treated subtype C-infected patients (P < 0.0001). The average mutation rates were 1.26 and 1.67 per patient for subtypes B and C, respectively (P = 0.036). The frequency of nucleoside associated mutations, but not M184V, in treated patients was significantly higher in subgroup B-infected patients (P = 0.028). Conclusion: Collectively, these data indicate that genetic variation at NNRTI resistance-associated positions such as V106M and A98S is substantially greater in subtype C-infected patients than in subtype B-infected patients. The natural structure of each subtype probably affects the frequency and pattern of drug resistance mutations selected under treatment.


Retrovirology | 2009

Tracing the HIV-1 subtype B mobility in Europe: a phylogeographic approach

Dimitrios Paraskevis; Oliver G. Pybus; Gkikas Magiorkinis; Angelos Hatzakis; Annemarie M. J. Wensing; David A. M. C. van de Vijver; Jan Albert; Birgitta Åsjö; Claudia Balotta; Enzo Boeri; Ricardo Jorge Camacho; Marie-Laure Chaix; Suzie Coughlan; Dominique Costagliola; Andrea De Luca; Carmen de Mendoza; Inge Derdelinckx; Zehava Grossman; O Hamouda; I. M. Hoepelman; Andrzej Horban; Klaus Korn; Claudia Kücherer; Thomas Leitner; Clive Loveday; E MacRae; I. Maljkovic-Berry; Laurence Meyer; Claus Nielsen; Eline Op de Coul

BackgroundThe prevalence and the origin of HIV-1 subtype B, the most prevalent circulating clade among the long-term residents in Europe, have been studied extensively. However the spatial diffusion of the epidemic from the perspective of the virus has not previously been traced.ResultsIn the current study we inferred the migration history of HIV-1 subtype B by way of a phylogeography of viral sequences sampled from 16 European countries and Israel. Migration events were inferred from viral phylogenies by character reconstruction using parsimony. With regard to the spatial dispersal of the HIV subtype B sequences across viral phylogenies, in most of the countries in Europe the epidemic was introduced by multiple sources and subsequently spread within local networks. Poland provides an exception where most of the infections were the result of a single point introduction. According to the significant migratory pathways, we show that there are considerable differences across Europe. Specifically, Greece, Portugal, Serbia and Spain, provide sources shedding HIV-1; Austria, Belgium and Luxembourg, on the other hand, are migratory targets, while for Denmark, Germany, Italy, Israel, Norway, the Netherlands, Sweden, Switzerland and the UK we inferred significant bidirectional migration. For Poland no significant migratory pathways were inferred.ConclusionSubtype B phylogeographies provide a new insight about the geographical distribution of viral lineages, as well as the significant pathways of virus dispersal across Europe, suggesting that intervention strategies should also address tourists, travellers and migrants.


Journal of Clinical Microbiology | 2008

Rapid Detection of blaKPC Carbapenemase Genes by Real-Time PCR

Musa Hindiyeh; Gill Smollen; Zehava Grossman; Daniela Ram; Yehudit Davidson; Fernando Mileguir; Marina Vax; Debbie Ben David; Ilana Tal; Galia Rahav; Ari Shamiss; Ella Mendelson; Nathan Keller

ABSTRACT Carbapenem resistance among Enterobacteriaceae is an emerging problem worldwide. Klebsiella pneumoniae carbapenemase (blaKPC) enzymes are among the most common β-lactamases described. In this study, we report the development and validation of a real-time PCR (q-PCR) assay for the detection of blaKPC genes using TaqMan chemistry. The q-PCR amplification of blaKPC DNA was linear over 7 log dilutions (r2 = 0.999; slope, 3.54), and the amplification efficiency was 91.6%. The q-PCR detection limit was 1 CFU, and there was no cross-reaction with DNA extracted from several multidrug-resistant bacteria. Perianal/rectal swabs (n = 187) collected in duplicate from 128 patients admitted to Sheba Medical Center surgical intensive care units were evaluated for the presence of carbapenem-resistant bacteria by culturing on MacConkey agar-plus-carbapenem disks and for blaKPC genes by q-PCR. Carbapenem-resistant organisms, all K. pneumoniae, were isolated from 47 (25.1%) of the 187 samples collected, while blaKPC genes were detected in 54 (28.9%) of the patient samples extracted by the NucliSENS easyMAG system. Of these, seven samples were positive for blaKPC genes by q-PCR but negative for carbapenem resistance by culture, while all samples in which no carbapenem-resistant bacteria were detected by culture also tested negative by q-PCR. Thus, the sensitivity and specificity of the q-PCR assay after extraction by the NucliSENS easyMAG system were 100% and 95%, respectively. Similar values were obtained after DNA extraction by the Roche MagNA Pure LC instrument: 97.9% sensitivity and 96.4% specificity. Overall, the blaKPC q-PCR assay appears to be highly sensitive and specific. The utilization of q-PCR will shorten the time to blaKPC detection from 24 h to 4 h and will help in rapidly isolating colonized or infected patients and assigning them to cohorts.


AIDS | 2001

Genotypic variation of HIV-1 reverse transcriptase and protease: comparative analysis of clade C and clade B.

Zehava Grossman; Nurit Vardinon; Daniel Chemtob; Michael Alkan; Zvi Bentwich; Michael Burke; Giora Gottesman; Valery Istomin; Itzchak Levi; Shlomo Maayan; Eduardo Shahar; Jonathan M. Schapiro

Objective To compare drug-resistant variants from untreated (naive) and treated patients infected with clade B or C virus. Methods Consecutive samples (165) from patients throughout Israel were analyzed. All those in the treated group were failing highly active antiretroviral therapy. Results There were 78 clade C (20 naive) and 87 clade B (14 naive) with significant differences in the prevalence of known drug-resistance mutations between the clades: in naive patients in the protease region M36I 7% and 95% (P < 0.0001), K20R 0% and 27% (P = 0.063), A71V 18% and 0% (P = 0.063), M46I 0% and 13%, and V77I 18% and 0% (P = 0.063), respectively, and in the reverse transcriptase region A98G/S 0% and 20% (P = 0.12), respectively. Most clade C viruses also showed significant differences from clade B consensus sequence at additional protease sites: R41K 100%, H69K/Q 85%, L89M 95% and I93L 80% (P < 0.0001). There were also significant differences (P < 0.03 to < 0.0001) in treated patients in clades B and C: in the protease region L10I 40% and 12%, M36I 26% and 95%, L63P 67% and 40%, A71I 38% and 7%, G73I and V77I 18% and 0%, I84V 16% and 3%, and L90M 40% and 12%, respectively; in the reverse transcriptase M41L 41% and 17%, D67N 41% and12%, K70R 30% and 7%, T215Y 48% and 29%, K219Q 21% and 7%, and A98G/S 3% and 24%, respectively. Conclusion Significantly differences between clade B and C viruses may be associated with development of differing resistance patterns during therapy and may affect drug utility in patients infected with clade C.


Journal of Acquired Immune Deficiency Syndromes | 2006

The Calculated Genetic Barrier for Antiretroviral Drug Resistance Substitutions Is Largely Similar for Different HIV-1 Subtypes

D.A.M.C. van de Vijver; A.M.J. Wensing; Gioacchino Angarano; Birgitta Åsjö; Claudia Balotta; Ricardo Jorge Camacho; M-L Chaix; Dominique Costagliola; A. De Luca; Inge Derdelinckx; Zehava Grossman; O Hamouda; Angelos Hatzakis; Robert Hemmer; Andy I. M. Hoepelman; Andrzej Horban; Klaus Korn; Claudia Kücherer; Thomas Leitner; Clive Loveday; E MacRae; I Maljkovic; C de Mendoza; Laurence Meyer; Carsten Uhd Nielsen; E.L.M. Op de Coul; V. Omaasen; Dimitrios Paraskevis; L Perrin; Elisabeth Puchhammer-Stöckl

Background: The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe. Methods: The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. Results: Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. Conclusions: Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.


Antimicrobial Agents and Chemotherapy | 2006

Discordances between Interpretation Algorithms for Genotypic Resistance to Protease and Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Are Subtype Dependent

Joke Snoeck; Rami Kantor; Robert W. Shafer; Kristel Van Laethem; Koen Deforche; Ap Carvalho; Brian Wynhoven; Marcelo A. Soares; Patricia A. Cane; John R. Clarke; Candice Pillay; Sunee Sirivichayakul; Koya Ariyoshi; África Holguín; H Rudich; Rosangela Rodrigues; María Belén Bouzas; Françoise Brun-Vézinet; Caroline Reid; Pedro Cahn; Luis Fernando de Macedo Brigido; Zehava Grossman; Vincent Soriano; Wataru Sugiura; Praphan Phanuphak; Lynn Morris; Jonathan Weber; Deenan Pillay; Amilcar Tanuri; Richard Harrigan

ABSTRACT The major limitation of drug resistance genotyping for human immunodeficiency virus remains the interpretation of the results. We evaluated the concordance in predicting therapy response between four different interpretation algorithms (Rega 6.3, HIVDB-08/04, ANRS [07/04], and VGI 8.0). Sequences were gathered through a worldwide effort to establish a database of non-B subtype sequences, and demographic and clinical information about the patients was gathered. The most concordant results were found for nonnucleoside reverse transcriptase (RT) inhibitors (93%), followed by protease inhibitors (84%) and nucleoside RT inhibitor (NRTIs) (76%). For therapy-naive patients, for nelfinavir, especially for subtypes C and G, the discordances were driven mainly by the protease (PRO) mutational pattern 82I/V + 63P + 36I/V for subtype C and 82I + 63P + 36I + 20I for subtype G. Subtype F displayed more discordances for ritonavir in untreated patients due to the combined presence of PRO 20R and 10I/V. In therapy-experienced patients, subtype G displayed a lot of discordances for saquinavir and indinavir due to mutational patterns involving PRO 90 M and 82I. Subtype F had more discordance for nelfinavir attributable to the presence of PRO 88S and 82A + 54V. For the NRTIs lamivudine and emtricitabine, CRF01_AE had more discordances than subtype B due to the presence of RT mutational patterns 65R + 115 M and 118I + 215Y, respectively. Overall, the different algorithms agreed well on the level of resistance scored, but some of the discordances could be attributed to specific (subtype-dependent) combinations of mutations. It is not yet known whether therapy response is subtype dependent, but the advice given to clinicians based on a genotypic interpretation algorithm differs according to the subtype.

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Klaus Korn

University of Erlangen-Nuremberg

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Jurgen Vercauteren

Rega Institute for Medical Research

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Andrzej Horban

Medical University of Warsaw

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H Rudich

Sheba Medical Center

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Anne-Mieke Vandamme

Rega Institute for Medical Research

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Koen Deforche

Rega Institute for Medical Research

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