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Fourth European HIV Drug Resistance Workshop, Monte Carlo, Monaco, 29-31 March 2006

 

Part 1 by Stephan Dressler, Berlin

 

The 4th European HIV Drug Resistance Workshop brought together about 350 virologists, clinicians, epidemiologists and representatives from the ppharmaceutical and diagnostic industry. The EATG is represented by Nikos Dedes who is member of the organising comittee. Out of more than 100 oral presentations and posters, we can highlight only a few in our report.

 

 

Section 1: Epidemiology of HIV Resistance

 

The first presentation by Luc Perrin from Geneva highlighted the fact that transmitted resistance currently does not seem to increase in Europe. An average of not more than 10% of newly acquired HIV infections are infections with virus harboring resistance-associated mutations. These mutations have a high tendency to persist even after treatment interruption. In contrast, resistance-associated mutations which developped under antiretroviral therapy are likely to return to wild-type virus after treatment interruption. However, transmission of virus carrying resistance-associated mutations maybe higher in some settings where large groups of ART-experienced patients live and can be dependent on the patient group analysed (for details, see below).

For the first time, results of the SPREAD programme were presented publicly. SPREAD is an official European Commission supported surveillance programme that collects prospectively representative data of newly diagnosed individuals and analyses in a systemic manner the spread of drug resistant HIV-strains and the distribution of various HIV-subtypes across Europe. In 2002/2003, 1083 newly diagnosed individuals from 17 European countries were included in whom subtype B was predominant with 66% (subtype A 9%). 9,1% of individuals were infected with drug resistant HIV. The prevalence of NRTI mutations was 5.4%, prevalence of PI mutations 3.0%, and that of NNRTI mutations 2.6%. 1 out of 3 NRTI resistant strains harbored more than 1 NRTI mutation. Less than 1% was infected with a dual class resistant strain. Patients infected in or originating from a high prevalence country had a lower risk of being infected with a drug-resistant strain. Prevalence of transmitted resistance was not significantly higher in seroconverters than in patients with unknown duration of infection [Wensing Abstract 11].

As part of the SPREAD programme, patterns of predicted drug susceptibility across Europe are analysed in the CAPTURE study. CAPTURE stands for Combined Analysis of the Prevalence of Therapy resistance during Use of antiretroviral drugs in Europe and included 1988 HIV protease and RT sequences collected in clinical practice from 2000 onwards in 14 European countries. Drug susceptibility was predicted using Retrogam 1.6 which ranks drugs using four categories from A (fully susceptible) to D (resistant). Reduced drug susceptibility was most frequently predicted for NRTIs and ranged among individual NRTIs from 37.0% (tenofovir) to 69.2% (didanosine). Medium or high level resistance was commonly predicted for the NNRTIs efavirenz and nevirapine (53.5%). For PIs, resistance was generally the least common, going from 22.1% (Lopinavir/r) to 40.8% (Nelfinavir). The authors point out that reduced susceptibility to all antiretroviral drugs was found in just 7.1% of the isolates. No sequence had high-level resistance to all antiretrovirals. Medium or high-level resistance decreased over time for all drugs with the exception of NNRTIs [Van de Vijver Abstract 4].

As part of the SPREAD programme, WATCH is a worldwide database project for collecting and analysing data on transmission of drug resistant HIV. Importantly, WATCH has been able to analyse the 6054 sequences collected so far from more than 60 research groups by using standardised methods. 451 sequences (7.05%) carried at least one resistance related mutation; 291 (5.33%) carried a mutation related to NRTI resistance, 151 (2.77%) had a mutation related to NNRTI resistance and 183 sequences (3.15%) carried PI-resistance-related mutations [Bowles Abstract 5, Poster 4].

These studies which gave a broader picture of the epidemiological situation of transmitted resistant virus were accompanied by a variety of studies in special populations and/or situations from various countries. Masquelier et al. from Bordeaux, France presented the analysis of a case of an infection with a dual-tropic, multidrug resistant HIV-1 which lead to rapid immunodeficiency [Abstract 7], thus reminding the audience of last year’s so-called ‘New York Case’. From Germany came a report on high levels of resistant HIV-1 in newly diagnosed patients (both with documented seroconversion and with unknown date of infection), showing transmission rates of resistant HIV-1 in seroconverters of 14%, and in newly diagnosed HIV patients of 13% [Kücherer Abstract 10]. In Berlin, the frequencies of transmission of resistant HIV in the inner city and in the periphery were 15.9% and 11.1%, respectively [Poggensee Abstract 14]. An analysis of 200 patients from Londons Royal Free Hospital demonstrated an overall-occurance of resistance-associated mutations in about 7%, differing widely between different patient groups and being highest in homosexuals. A multicentre study had previously suggested much higher levels of resistance to any drug of up to 19% for the UK but this number could indicate possible patient selection bias [Booth Abstract 11]. The 1999-2005 analysis of a larger cohort in Spain suggests a decrease in the number of resistance mutations to NRTIs and PIs in antiretroviral experienced patients over time while NNRTI resistance mutations tend to increase. These findings could be explained by changes in the prescribed NRTI (i.e. tenofovir, abacavir) and use of boosted PIs and the widespread use of efavirenz for an increase of K103N mutations [Garcia-Leon Abstract 15]. A small study from Madrid with 41 ART-naïve HIV-infected patients found resistance-associated mutations in 7.3% (3/41) [Garcia Abstract 29].

 

 

Section 2: Resistance to Entry Inhibitors

 

A.M. Vandamme from Belgium provided an update on clinical aspects of CCR5 inhibitors, focusing on the mechanisms of tropism shift and resistance development. Resistance to CCR5 inihibitors has been demonstrated, independent of a switch to the CXCR4 receptor or of a selection of CXCR4-tropic virus. Fundamental for this resistance-associated mutation seems to be a change in the env region of HIV which allows the virus to use CCR5 co-receptors even in the presence of a CCR5 inhibitor. Potentially, CCR5 inhibitors have a synergy with enfuvirtide (T20) and may even inhibit enfuvirtide resistant CCR5-tropic virus. Several presentations focussed on the challenges in prediction of HIV-1 coreceptor usage. Possibly, immunologic markers (like CD4/CD8 ratio) or additional genetic analysis (V3 sequence) may be helpful tools. Currently, much more research seems to be needed to understand the mechanisms of tropism change and resistance development to CCR5 inhibitors.

Currently, enfurvitide (T20) is the only approved entry inhibitor. Resistance to T20 is primarily conferred by mutations in the HR-1 region of gp41, a protein from HIV. Despite virologic failure, there can be a significant increase in CD4 cells. A possible explanation for this observation could be that a change in gp41 results in a loss of fusion efficiency upon cell targets and creates new epitopes which chalenge an immune-mediated response [Svicher Abstract 32, Micheli Abstract 38].

 

 

Section 3: NRTI and PI Resistance (Part 1)

 

Possibly the most interesting session from a clinical point of view, much information was provided in form of posters and abstracts. In focus were certainly presentations on tipranavir (the most recently approved PI, tradename Aptivus) and TMC114, Tibotech’s PI which recently entered Expanded Access Programmes in Europe. According to a study presented by L. Bacheler from VircoLab [Abstract 40], viral isolates from a highly treatment experienced population (from Resist 1 and 2 trials) with clinically relevant resistance to older PIs retain at least partial susceptibility to Tipranavir. 21 mutations at 16 amino acid locus are associated with resistance to Tipranavir which the current prediction algorithm of tipranavir susceptibility from genotype uses. But this currently available genotypic algorithm does not fully capture the effects of all mutations impacting in vitro susceptibility. E.P. Coakley from Monogram Biosciences identified additional PR mutations that can contribute to a more accurate Tipranavir genotype interpretation algorithm [Abstract 41]. In a resistance cohort from Granada, Spain, no tipranavir-resistant strains were found even for lopinavir/r, atazanavir/r or fosamprenavir/r resistant isolates among 578 PI-experienced patients [Casanas Carillo Abstract 50].

Tibotech-driven presentations focussed on the PI TMC114 and were not only emphasizing its efficacy, but also provided some - preliminary - data on resistance which are sometimes difficult to interpret because of the way how they were presented. S. De Meyer reported from 586 samples with decreased susceptibility to TMC114 [Abstract 42] out of 9,968 clinical isolates (from the Power trials?). Out of these 586 samples, 0,5% were susceptible to lopinavir, and 53% susceptible to tipranavir. Also, the majority of samples with decreased susceptibility to lopinavir and tipranavir remained susceptible to TMC114. There seems to be no or only limited cross-resistance between TMC114 and tipranavir, since isolates from virologic failure (Power studies) that were sensitive to tipranavir at baseline remained sensitive to tipranavir [Bethune Abstract 51].

 

Source:

Fourth European HIV Drug Resistance Workshop, Monte Carlo, Monaco, 29-31 March 2006. Programme & Abstracts. Book. Information also accessible at http://www.virology-education.com

 

Additional information:

Strategies for the Management of Multiclass-Resistant Patients. Clinical Care Options HIV 2005. http://www.clinicaloptions.com/multiclass (Provides treatment-oriented information and discussion of resistance)

Wolf, Eva: HIV Resistance Testing. In: Hoffmann, Rockstroh, Kamps (eds): HIV Medicine 2005, p 311-330. Wuppertal: Steinhäuser Verlag 2005. http://www.HIVMedicine.com (Provides a summary of the different assays and interpretations)

Clotet B (ed.): Guide to Management of HIV Drug Resistance, Antiretrovirals Pharmacokinetics and Viral Hepatitis in HIV Infected Subjects. Barcelona: Fundació de Lluita contra la SIDA, Fifth edition 2005. http://www.flsida.org (Provides almost everything you need to know about resistance.)