New Rising Infection: Human Herpesvirus 6 Is Frequent in Myeloma Patients Undergoing Autologous Stem Cell Transplantation after Induction Therapy with Bortezomib

Herpesvirus 6 (HHV-6) infection is a common complication during immunosuppression. Its significance for multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) after treatment with novel agents affecting immune system remains undetermined. Data on 62 consecutive MM patients receiving bortezomib-dexamethasone (VD) (; 66%) or thalidomide-dexamethasone (TD) (, 34%) induction, together with melphalan 200 mg/m2 autograft between 01.2005 and 09.2010, were reviewed. HHV-6 reactivation was diagnosed in patients experiencing postengraftment unexplained fever (PEUF) in the presence of any level of HHHV-6 DNA in blood. There were no statistically significant differences in patient characteristics between the groups, excluding dexamethasone dosage, which was significantly higher in patients receiving TD. Eight patients in TD and 18 in VD cohorts underwent viral screening for PEUF. HHV-6 reactivation was diagnosed in 10 patients of the entire series (16%), accounting for 35% of those screened; its incidence was 19.5% () in the VD group versus 9.5% () in the TD group. All patients recovered without sequelae. In conclusion, HHV-6 reactivation is relatively common after ASCT, accounting for at least a third of PEUF episodes. Further studies are warranted to investigate whether bortezomib has an impact on HHV-6 reactivation development

Comparable long-term efficacy of Lopinavir/Ritonavir and similar drug-resistance profiles in different HIV-1 subtypes.

BACKGROUND: Analysis of potentially different impact of Lopinavir/Ritonavir (LPV/r) on non-B subtypes is confounded by dissimilarities in the conditions existing in different countries. We retrospectively compared its impact on populations infected with subtypes B and C in Israel, where patients infected with different subtypes receive the same treatment. METHODS: Clinical and demographic data were reported by physicians. Resistance was tested after treatment failure. Statistical analyses were conducted using SPSS. RESULTS: 607 LPV/r treated patients (365 male) were included. 139 had HIV subtype B, 391 C, and 77 other subtypes. At study end 429 (71%) were receiving LPV/r. No significant differences in PI treatment history and in median viral-load (VL) at treatment initiation and termination existed between subtypes. MSM discontinued LPV/r more often than others even when the virologic outcome was good (p = 0.001). VL was below detection level in 81% of patients for whom LPV/r was first PI and in 67% when it was second (P = 0.001). Median VL decrease from baseline was 1.9±0.1 logs and was not significantly associated with subtype. Median CD4 increase was: 162 and 92cells/µl, respectively, for patients receiving LPV/r as first and second PI (P = 0.001), and 175 and 98, respectively, for subtypes B and C (P<0.001). Only 52 (22%) of 237 patients genotyped while under LPV/r were fully resistant to the drug; 12(5%) were partially resistant. In48%, population sequencing did not reveal resistance to any drug notwithstanding the virologic failure. No difference was found in the rates of resistance development between B and C (p = 0.16). CONCLUSIONS: Treatment with LPV/r appeared efficient and tolerable in both subtypes, B and C, but CD4 recovery was significantly better in virologically suppressed subtype-B patients. In both subtypes, LPV/r was more beneficial when given as first PI. Mostly, reasons other than resistance development caused discontinuation of treatment

HCV genotype-1 subtypes and resistance-associated substitutions in drug-naive and in direct-acting antiviral treatment failure patients

Background: Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions. Methods: In a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Posttreatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure. Results: GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first-and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations. Conclusions: NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy

A Population-Structured HIV Epidemic in Israel: Roles of Risk and Ethnicity

<div><p>Background</p><p>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.</p><p>Methods</p><p>We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998–2012. HIV phylogenies were reconstructed with maximum-likelihood and Bayesian methods.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>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.</p></div

Viral load and CD4 counts at the beginning and the end of the study.

<p>Patients were grouped as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086239#pone-0086239-t003" target="_blank">Table 3</a>. The median of the individual CD4 changes, ΔCD4, was calculated for each group (rather than the difference between the medians of CD4 counts). Selected <i>p</i>-values between relevant groups are shown. Significant differences between groups in other parameters were not found.</p><p>Abbreviations: 1st_PI – patients receiving LPV/r as first PI; 2nd _PI – patients receiving LPV/r as second or higher-order PI; B – patients with HIV subtype B; C – patients with HIV subtype C; C_M – male patients with subtype C; F –female; F-UP – follow up, time from diagnosis to start of the study, in years; M– male; MSM – men who have sex with Men; non-BC- patients with HIV subtype other than subtype B or C; PI – protease inhibitor; VL – viral load; a</p><p><i>p</i> values were calculated between groups in the box. The C or non-BC groups were compared to the B group.</p>b<p>the median values of the individual ΔCD4 values of patients.</p

Clinical outcome of LPV/r treatment of patients stratified according to different VL and CD4 levels at baseline.

<p>Patients were stratified according to VL: above 100,000 cp/ml; between 10 and 100 thousands cp/ml and below 10,000 cp/ml when starting LPV/r. Each group was further divided according to baseline CD4 count: below 200 cells/µl; between 200 and 500 cells/µl and above 500 cell/µl, creating altogether 9 groups. Group 9 (VL below 10,000 cp/ml and CD4 counts more than 500 cell/µl) was significantly different from the other groups in two parameters: shorter time on LPV/r treatment and lower percent of patients receiving LPV/r as first PI. As the median VL of this group was initially below detection level and baseline CD4 count above 700, no further decline in viral load could be observed and the lack of further increase in CD4 was also expected.</p><p>cp/ml – copies/ml; Gr – group; VL –Viral Load.</p

Resistance status of patients failing LPV/r.

<p>Clinical resistance status of 237 patients failing cART including LPV/r was determined according to the True-gene™ software (version 10). The last available sample under LPV/r from each patient was used.</p

Partition of the viral-loads of treatment-failing patients into “high” and “low” categories.

<p>Shown are box-plots indicating partition of the viral-load distributions at treatment failure for those who failed either with or without mutations. Each plot shows median, quartiles and range. Viral load is expressed in copies/ml plasma. Dashed line – viral load cutoff, at 6,000 copies/ml. Mut – resistance conferring mutations; n – number; No-mut – No resistance conferring mutations; PI – Protease Inhibitor.</p

Mutation patterns in LPV/r failing C patients from Israel and South Africa.

<p>The table lists all mutation patterns that appeared more than once in the combined dataset of 101 samples, 55 from South Africa (van Zyl <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086239#pone.0086239-VanZyl1" target="_blank">[33]</a>) and 46 from Israel (this study). Fifty nine samples (58% of total) included 16 patterns. The actual frequency (number of times a pattern appeared in the dataset) and the calculated frequency (based on the overall frequencies of each mutation included in that pattern, assuming independence) for the most prevalent patterns are compared. <i>p</i>-values were calculated using Fisher's two- tailed Exact Test. IL – Israel; SA – South Africa.</p