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Avidor B.,Laboratory for Viruses and Molecular Biology | Avidor B.,Crusaid Kobler Center | Girshengorn S.,Laboratory for Viruses and Molecular Biology | Girshengorn S.,Crusaid Kobler Center | And 25 more authors.
Journal of Clinical Microbiology | Year: 2013

Detection of low-abundance drug resistance mutations (DRMs) of HIV-1 is an evolving approach in clinical practice. Ultradeep pyrosequencing has shown to be effective in detecting such mutations. The lack of a standardized commercially based assay limits the wide use of this method in clinical settings. 454 Life Sciences (Roche) is developing an HIV ultradeep pyrosequencing assay for their benchtop sequencer. We assessed the prototype plate in the clinical laboratory. Plasma samples genotyped by the standardized TruGene kit were retrospectively tested by this assay. Drug-treated subjects failing therapy and drug-naive patients were included. DRM analysis was based on the International AIDS Society USA DRM list and the Stanford algorithm. The prototype assay detected all of the DRMs detected by TruGene and additional 50 low-abundance DRMs. Several patients had lowabundance D67N, K70R, and M184V reverse transcriptase inhibitor mutations that persisted long after discontinuation of the drug that elicited these mutations. Additional patient harbored low-abundance V32I major protease inhibitor mutation, which under darunavir selection evolved later to be detected by TruGene. Stanford analysis suggested that some of the low-abundance DRMs were likely to affect the resistance burden in these subjects. The prototype assay performs at least as well as TruGene and has the advantage of detecting low-abundance drug resistance mutations undetected by TruGene. Its ease of use and lab-scale platform will likely facilitate its use in the clinical laboratory. The extent to which the detection of low-abundance DRMs will affect patient management is still unknown, but it is hoped that use of such an assay in clinical practice will help resolve this important question. Source

Turner D.,Crusaid Kobler Center | Amit S.,Crusaid Kobler Center | Chalom S.,Crusaid Kobler Center | Penn O.,Tel Aviv University | And 8 more authors.
HIV Medicine | Year: 2012

Objective: Drug resistance-associated mutations (DRMs) among HIV-1 treatment-naïve patients have increased in recent years. Their incidence and prevalence in various exposure risk categories (ERCs) were evaluated. Design: Plasma samples of HIV-1 treatment-naïve patients diagnosed between 2001 and 2009 at the Tel Aviv Medical Center were screened for DRMs. Methods: Samples obtained from patients following the HIV diagnosis were analysed retrospectively. Genotyping was carried out using the Trugene HIV-1 genotype kit (Siemens, Berkeley, CA, USA). Phylogenetic relationships among viral sequences were estimated using the maximum likelihood method. Results: Thirty-eight of the 266 analysed sequences (14.3%) had DRMs, all occurring exclusively in the group of men who have sex with men (MSM). The rate of DRMs has constantly risen, reaching a peak of 21.9% in 2009. Notably, protease inhibitor (PI) DRMs became the most frequent DRMs in 2009. Phylogenetic analysis showed a tight cluster comprising 13 of 14 viruses harbouring the L90M major PI resistance mutation, suggesting a single infection source. Conclusion: There was an unexpectedly high rate of the major L90M PI resistance mutation in the MSM group. The clustered transmission of this mutation might be related to a high-risk sexual behaviour. Added to nonnucleoside reverse transcriptase inhibitor and nucleoside reverse transcriptase inhibitor resistance mutations, such a PI mutation may limit future therapeutic options for this particular patient population. © 2011 British HIV Association. Source

Grossman Z.,Tel Aviv University | Grossman Z.,U.S. National Cancer Institute | Avidor B.,Crusaid Kobler Center | Avidor B.,Tel Aviv Sourasky Medical Center | And 24 more authors.
PLoS ONE | Year: 2015

Background: HIV in Israel started with a subtype-B epidemic among men who have sex with men, followed in the 1980s and 1990s by introductions of subtype C from Ethiopia (predominantly acquired by heterosexual transmission) and subtype A from the former Soviet Union (FSU, most often acquired by intravenous drug use). The epidemic matured over the last 15 years without additional large influx of exogenous infections. Between 2005 and 2013 the number of infected men who have sex with men (MSM) increased 2.9-fold, compared to 1.6-fold and 1.3-fold for intravenous drug users (IVDU) and Ethiopian-origin residents. Understanding contemporary spread is essential for effective public health planning. Methods: We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998-2012. HIV phylogenies were reconstructed with maximumlikelihood and Bayesian methods. Results: Subtype-B viruses, but not A or C, demonstrated a striking number of large clusters with common ancestors having posterior probability ≥0.95, including some suggesting presence of transmission networks. Transmitted drug resistance was highest in subtype B (13%). MSM represented a frequent risk factor in cross-ethnic transmission, demonstrated by the presence of Israeli-born with non-B virus infections and FSU immigrants with non-A subtypes. Conclusions: Reconstructed phylogenetic trees demonstrated substantial grouping in subtype B, but not in non-MSM subtype-A or in subtype-C, reflecting differences in transmission dynamics linked to HIV transmission categories. Cross-ethnic spread occurred through multiple independent introductions, with MSM playing a prevalent role in the transmission of the virus. Such data provide a baseline to track epidemic trends and will be useful in informing and quantifying efforts to reduce HIV transmission. © This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Source

Avidor B.,Crusaid Kobler Center | Avidor B.,Sourasky Tel Aviv Medical Center | Turner D.,Crusaid Kobler Center | Mor Z.,Public Health Services | And 17 more authors.
PLoS ONE | Year: 2013

Background: HIV subtypes A and CRF01_AE (A/AE) became prevalent in Israel, first through immigration of infected people, mostly intravenous-drug users (IVDU), from Former Soviet-Union (FSU) countries and then also by local spreading. We retrospectively studied virus-transmission patterns of these subtypes in comparison to the longer-established subtype B, evaluating in particular risk-group related differences. We also examined to what extent distinct drug-resistance patterns in subtypes A/AE versus B reflected differences in patient behavior and drug-treatment history. Methods: Reverse-transcriptase (RT) and protease sequences were retrospectively analyzed along with clinical and epidemiological data. MEGA, ClusalX, and Beast programs were used in a phylogenetic analysis to identify transmission networks. Results: 318 drug-naive individuals with A/AE or patients failing combination antiretroviral therapy (cART) were identified. 61% were IVDU. Compared to infected homosexuals, IVDU transmitted HIV infrequently and, typically, only to a single partner. 6.8% of drug-naive patients had drug resistance. Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations. Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype. Conclusions: While sizable transmission networks occur in infected homosexuals, continued HIV transmission among IVDU in Israel is largely sporadic and the rate is relatively modest, as is that of drug-resistance transmission. Deviation of drug-naive A/AE sequences from subtype-B consensus sequence, documented here, may subtly affect drug-resistance pathways. Conspicuous differences in overall drug-resistance that are manifest before regimen stratification can be largely explained in terms of treatment history, by the different efficacy/adherence limitations of older versus newer regimens. The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation. © 2013 Avidor et al. Source

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