HTB

Report from the 10th Annual UK Resistance Meeting, 21 September 2006, London

7 October 2006. Related: Conference reports, Drug resistance, .

Svilen Konov, HIV i-Base

This year’s Annual UK Resistance Meeting was held on 21 September in London. Faculty were Professor Jonathan Weber, FRCP Imperial College, London and Dr Anna Maria Geretti from Royal Free Hospital, London.

The meeting has been traditionally known for its high quality and opportunity to see the presentations of leading specialists in the field. This year was no exception. This report covers six of the oral presentations.

Garcia-Diaz and colleagues from the Royal Free Hospital and UCL Medical School in London genotyped 239 (169 male, 50% white) subjects with early infection (seroconversion within 4-5 months, shown by a detuned HIV antibody test) in order to characterise the resistance rates. [1]

The subtype distribution was 56%-B, 19%-C, 7%-A, and 12%-other non-B (CRF02, D, G, CRF01, CRF 06, CRF13, CRF16). Resistance mutations were detected in 17 subjects (7.1%), 15 UK born, 1 from South Africa, and 1 from Pakistan. The prevalence by drug class was: NRTI 10/239 (mainly TAMs), NNRTI 4/239 (exclusively K103N), PI 4/239 (M46L, V82L, L90M). One person had both NRTI and PI mutations. The researchers concluded that the prevalence of primary resistance was significant, in this group mainly restricted to people born in the UK.

Cozzi-Lepri from University College London and a team of international collaborators compared 9 existing rule-based genotype interpretation systems for abacavir (ANRS, CHL, Detroit, Stanford, QUEST, Rega, Retrogram, Sao Paolo, and TRUGENE). [2]

1306 patients with a viral load >500 copies/mL and who had a genotypic test at the time of starting an abacavir-containing regimen were included. The median number of abacavir-associated resistance mutations was 3 (range 0-7). The median week 8 viral load reduction was 1.61 log 10 copies/mL. Most of the interpretation systems, however, showed larger viral load reductions in patients classified as sensitive compared to intermediate or resistant. The team highlighted the issue that there is still a high degree of variability in predicting susceptibility to abacavir between different interpretation systems..

Winters and colleagues from Virco and Tibotec presented clinical cut-offs for darunavir (TMC114). [3]

They used a multiple linear regression model to predict the darunavir fold change from the viral genotype and a linear regression model that used the data from the POWER 1, 2, and 3 studies to predict the 8-week change in viral load on regimens containing ritonavir-boosted darunavir. This model was used to define two clinical cut-offs linked to predicted darunavir fold-change values, associated with 20 or 80% loss of the darunavir/r response, for subjects infected with wild type strains. The 20% and 80% loss of wildtype darunavir response were predicted at 3.4 and 97 fold change respectively. Detailed reports on resistance and sensitivity to darunavir were included in reports from this years International Resistance Workshop in the July/August issue of HTB. [4]

Booth CL and researchers from Royal Free Hospital and UCL Medical School together with people from Virco looked into the inter-laboratory reproducibility of the identification of resistance-associated mutations and pol-derived HIV-1 subtyping. [5]

The team tested 65 samples by ViroSeq and by Virco’s in-house assay. As some samples did not yield a sequence the total number of paired genotypes achieved was 57. Among them 1 (2%) showed no resistance mutations, 9 (16%) showed a resistance mutation by one assay and a mixture of the same mutant with wild-type by the other. In general, concordance was good, but not perfect.

As abacavir/3TC is a commonly used as a backbone nowadays, Reddy HV and colleagues from Hull York Medical School and the Virology Department of the Leeds teaching hospitals, investigated retrospectively the frequent early failures of regimens containing this dual-nucleoside backbone. [6]

They reviewed the case notes of 8 patients who started on abacavir/3TC, four of whom achieved durable complete viral suppression. Three patients had a virological relapse within 2-4 months despite good adherence, and lack of serious adverse events and resistance at baseline. The three patients were male, two with a subtype C and one with a subtype B. Two of them used efavirenz and one used nevirapine. The resistance tests at rebound showed K65R (in all three), L74V (in one), Y181C (in one), and G190E (in two). Even though a large prospective randomised trial demonstrated that abacavir/3TC plus an NNRTI is an efficient treatment, there are instances when the clinical practice is at odds with the conclusions of that study and those call for further exploration.

Another study from Royal Free Hospital (Booth and colleagues) looked into the prevalence of drug resistance in patients with viral load above 50 and below 5000 copies. [7]

Among the 2000 people who were followed in the study, 100 were within the above-mentioned virological range. The most common mutations discovered were:

RT: M184V (in 30%), K103N (in 21%), D67N (in 16%), T215Y (in 16%), M41L (in 15%), K70R (in 15%), K219Q/E (in 15%), L210W (in 6%), and Y181C (in 5%)

PR: L90M (in 10%), I84V (in 7%), M46I (in 5%), and I54V (in 5%)

The study shows that even if the prevalence of resistance is high, it is not universal in patients failing HAART with a viral load of <5000 copies/mL.

References:

Unless stated otherwise, all references are to the programme and abstracts for the 10th Annual Resistance Meeting, 21 September 2006, London.

  1. Garcia-Diaz A, Booth C et al. Being born in the UK is an independent predictor of transmitted drug resistance in London. Abstract 1.
  2. Cozzi-Lepri A, Phillips AN et al. Initiatives for developing and comparing genotype interpretation systems (step 1): external validation of existing rules-based interpretation systems for abacavir against virologic response. Abstract 2.
  3. Winters B, Vermeiren H et al. Development of Virco®TYPE resistance analysis, including clinical cut-offs, for TMC114. Abstract 3.
  4. Resistance to darunavir (TMC-114): predicting responses for treatment experienced patients. HIV Treatment Bulletin July/August 2006.
    http://www.i-base.info/htb/2344
  5. Booth CL, Ramaswamy M et al Inter-laboratory reproducibility of the identification of resistance-associated mutations and pol-derived HIV-1 subtyping. Abstract 4.
  6. Reddy HV, Hale A et al. Frequent early failure of Kivexaĭcontaining regimes associated with emergence of K65R. Abstract 5.
  7. Booth CL, Garcia-Diaz A et al. Prevalence of antiretroviral drug resistance mutations in patients with viral load above 50 and below 5000 copies/mL while on HAART. Abstract 6.

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