Suchergebnisse

IntroductionSimeprevir, a new oral NS3/4A protease inhibitor, was recently approved by the FDA and the EMA for the treatment of patients with chronic HCV genotype 1, 4, 5 and 6 infection l. It has been recommended in the 2014 UK Consensus Guidelines as a possible treatment of previously untreated genotype 1a‐infected patients. The antiviral efficacy of simeprevir is adversely affected by the mutation at the Q80K loci. There is controversial discussion that the incidence of Q80K in the European HCV 1a‐infected community is very low and therefore testing of Q80K before starting a therapy including simeprevir is not necessary. We analyzed the appearance of Q80K in all sequenced HCV NS3A samples in 2014 in our laboratory.Materials and MethodsAll in 2014 received orders for HCV resistance tests were analyzed with an in‐house bulk sequencing method analyzing NS3A amino acids 1–181. Analysis was performed using geno2pheno HCV. The genotype 1a samples were selected, Q80K status and data of HIV co‐infection were collected.ResultsForty‐two HCV 1a samples were sent to us for resistance analyses from nine different medical centres in Berlin and Hannover, Germany. Nineteen (or 45%) of the sequences showed a Q80K mutation. Six extra clade I viruses had no Q80K mutation. Comparison between mono‐ and HIV‐1 co‐infected patients showed no difference in frequency of Q80K (mono‐infected: 8 out of 19 patients; co‐infected: 9 out of 23). For two 80K‐positive patients, the HIV‐status was not available.ConclusionsThe incidence for Q80K mutation in HCV genotype 1a with overall 45% is substantially high in our cohort and does not differ between mono‐ and HIV‐1 co‐infected patients. Response to simeprevir is affected by the presence of viral Q80K. When treating HCV‐infected patients with a simeprevir containing regimen, it is therefore important that HCV does not contain the Q80K mutation.

IntroductionRules‐based HIV‐1 drug‐resistance interpretation (DRI) systems disregard many amino‐acid positions of the drug's target protein. The aims of this study are (1) the development of a drug‐resistance interpretation system that is based on HIV‐1 sequences from clinical practice rather than hard‐to‐get phenotypes, and (2) the assessment of the benefit of taking all available amino‐acid positions into account for DRI.Materials and MethodsA dataset containing 34,934 therapy‐naïve and 30,520 drug‐exposed HIV‐1 pol sequences with treatment history was extracted from the EuResist database and the Los Alamos National Laboratory database. 2,550 therapy‐change‐episode baseline sequences (TCEB) were assigned to test set A. Test set B contains 1,084 TCEB from the HIVdb TCE repository. Sequences from patients absent in the test sets were used to train three linear support vector machines to produce scores that predict drug exposure pertaining to each of 20 antiretrovirals: the first one uses the full amino‐acid sequences (DEfull), the second one only considers IAS drug‐resistance positions (DEonlyIAS), and the third one disregards IAS drug‐resistance positions (DEnoIAS). For performance comparison, test sets A and B were evaluated with DEfull, DEnoIAS, DEonlyIAS, geno2pheno[resistance], HIVdb, ANRS, HIV‐GRADE, and REGA. Clinically‐validated cut‐offs were used to convert the continuous output of the first four methods into susceptible‐intermediate‐resistant (SIR) predictions. With each method, a genetic susceptibility score (GSS) was calculated for each therapy episode in each test set by converting the SIR prediction for its compounds to integer: S=2, I=1, and R=0. The GSS were used to predict therapy success as defined by the EuResist standard datum definition. Statistical significance was assessed using a Wilcoxon signed‐rank test.ResultsA comparison of the therapy‐success prediction performances among the different interpretation systems for test set A can be found in Table 1, while those for test set B are found in Figure 1. Therapy‐success prediction of first‐line therapies with DEnoIAS performed better than DEonlyIAS (p<10–16).ConclusionsTherapy success prediction benefits from the consideration of all available mutations. The increase in performance was largest in first‐line therapies with transmitted drug‐resistance mutations.

IntroductionDue to drug‐drug interactions of HIV‐ and HCV‐specific antivirals when initiating an HCV‐therapy, the antiretroviral therapy (ART) often has to be changed. The spectrum of applicable antiretrovirals is small, therefore many patients were switched to raltegravir/truvada (RAL/TVD) in our cohort. Due to the relatively low genetic barrier of RAL, this regimen may be endangered to fail, if the NRTI backbone is not fully active because of pre‐existing NRTI resistance. We investigated the long‐term follow‐up and safety of RAL/TVD in co‐infected patients after hepatitis C virus (HCV) therapy was stopped and the protective antiretroviral effect of interferon ended.Materials and MethodsTwenty patients initiated a direct‐acting antiviral (DAA) containing HCV therapy (8x faldaprevir, 6x telaprevir, 2x daclatasvir and 4x simeprevir) between 11/2011 and 01/2013. Seventeen were switched to RAL/TVD, three patients were not treated before, but started with the regimen. Diagnosis of HIV infection was dated between 1985 and 2010. The HI‐viral suppression was monitored retrospectively to date.ResultsThirteen of the twenty patients (65%) remained on RAL/TVD after finishing HCV treatment, for seven patients, no data about their ART continuation was available, after HCV therapy had stopped. All remaining thirteen patients showed an HI‐viral load below detection limit up to date (for 15 to 22 months, median 20 months). Only for four patients, historic resistance data were available but none showed NRTI mutations.ConclusionsSwitch to RAL/TVD as HIV ART due to initiating HCV therapy was safe for the observed small cohort even in long‐term follow‐up without switchback or a second ART switch. However, resistance data for the cohort was little, showing no NRTI mutations, indicating a relatively safe setting. Since no further data is available, physicians should keep in mind ART history, historical therapy failure and HIV‐resistance while switching ART to treat HCV in co‐infected patients. Further investigation in larger cohorts is needed, especially thinking of upcoming interferon‐free HCV regimen in heavily pre‐treated co‐infected patients.

IntroductionProven resistance against HIV drugs, either by phenotyping or genotyping is a rare event in clinical trials. The overall assumption of drug resistance disappearing is additionally driven by the recommendations to screen for transmitted drug resistance, leading to large numbers of examinations with relatively low rates of resistance. Goal of our analysis was to assess if drug resistance in treatment failure is also decreasing outside of clinical trials.Materials and MethodsThe MIB database at timepoint of analysis consists of data from 2876 HIV infected patients. Besides various laboratory parameters, clinical data and treatment history is included. HIV‐1 protease and reverse transcriptase sequences were analyzed using the HIV‐GRADE drug resistance algorithm. As in only a small number of patients genotypic resistance testing for integrase inhibitors was performed, mainly due to reimbursement reasons, it was assumed that failing treatment on a previous integrase inhibitor containing regimen is equate to resistance.ResultsOf the 2876 patients in the database, 220 had a treatment change due to treatment failure between 2009 and 2012, a genotypic resistance testing at an appropriate timepoint of maximum four weeks before treatment change and a treatment duration of at least six months before treatment failure. In 2009, 61% of patients showed no drug resistance while 39% showed resistance against one or more drug classes (two or more drug classes: 19.5%; three or more drug classes: 2.4%, four drug classes 2.4%). In 2012, no resistance was found in 52% of patients while resistance against three or more drug classes was found in nearly 14% of patients (one or more: 48%; two or more 23%; four classes: 4.5%).ConclusionsTreatment failure with viral load sufficiently high for drug resistance testing was not frequently observed in our database. Nevertheless, treatment failure was often associated with drug resistance against at least one drug class. With more use of the newer drug classes, resistance against those new classes will become more common and rates of multiclass resistance will be increasing.

IntroductionThe most recently approved antiretroviral, the integrase inhibitor dolutegravir (DTG), is described to be a very potent drug with a unique resistance profile, but a certain degree of cross‐resistance to RAL or EVG induced drug resistance, which is mediated mainly by integrase mutations at positions 140 and 148. The impact of a single N155H mutation to DTG resistance is described to be minor. However, there is only rare data available about the impact of N155H in the context of secondary site integrase mutations. Here, we present a case of virological failure in a DTG treated patient based on N155H mutation background.MethodsTherapy monitoring of an HIV‐HCV co‐infected patient harbouring already an omni‐drug‐class resistant HIV‐1 in consequence of more than 20 years ART history. Drug susceptibility testing was performed by RT‐PCR from plasma and subsequent Sanger sequencing. Tropism testing was done from proviral DNA with FPR cut‐offs according to the German recommendations.ResultsIn 2013, the patient harbouring a virus with high level resistance to all RTI and PI received a regimen containing FTC, TDF, DRV/r, RPV, T20, and RAL to handle a viral load of 5000 RNA copies/mL, but never achieved fully suppressed viral load. In June 2013, after S119R, N155H and E157Q mutations in viral integrase were detected, the patient received DTG, and RAL was stopped. One month later, when viral load was undetectable for the first time since 2007, ART was de‐escalated by removing T20. Since February 2014, low‐level viral load was re‐detectable. Two new mutations T97A and S147G in the integrase and no other new resistance associated mutations in protease and reverse transcriptase in comparison to the sample analyzed in June 2013 were detected.ConclusionsHighly resistant HIV‐1 strains have been a common problem in the past. Their frequencies were pushed back by highly potent ART, but the virus is still able to become resistant against all available antiretrovirals at once. The here documented strain became resistant to DTG without carrying mutations at the described positions 140 and 148, but in the context of integrase N155H. Since N155H alone is described not to contribute sufficient resistance to DTG, there seems to be a need to re‐check viruses with N155H plus minor mutations (like T97A, S119R, S147G and E157Q) potentially contributing to DTG resistance.