JAC Advance Access originally published online on June 13, 2008
Journal of Antimicrobial Chemotherapy 2008 62(3):464-468; doi:10.1093/jac/dkn228
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Original research |
Low prevalence of transmitted antiretroviral drug resistance in a large UK HIV-1 cohort
1 Department of Infection and Travel Medicine, James Cook University Hospital, Middlesbrough, UK 2 Department of Infectious Diseases and Sexual Health, Bradford Teaching Hospitals Foundation Trust, Bradford, UK 3 Department of Infection and Tropical Medicine, Newcastle General Hospital, Newcastle-upon-Tyne, UK 4 Department of Genitourinary Medicine, Royal Hallamshire Hospital, Sheffield, UK 5 South Yorkshire Regional Department of Infection and Tropical Medicine, Royal Hallamshire Hospital, Sheffield, UK 6 Department of Infection and Travel Medicine, St James’ Hospital, Leeds, UK 7 Department of Genitourinary Medicine, Newcastle General Hospital, Newcastle-upon-Tyne, UK 8 Department of Infection and Tropical Medicine, Castle Hill Hospital, Cottingham, East Yorkshire, UK
* Corresponding author: Tel: +44-1642-850850; Fax: +44-1642-854017; E-mail: davidr.chadwick{at}stees.nhs.uk
Received 30 December 2007; returned 27 March 2008; revised 8 May 2008; accepted 19 May 2008
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Abstract |
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Objectives: To describe current practice in testing for transmitted antiretroviral drug resistance (TDR) and the prevalence of TDR in a large UK HIV-1 cohort.
Methods: The study includes a retrospective analysis of newly diagnosed HIV-1-infected patients presenting to eight HIV clinics in the north of England between March 2005 and March 2007. Resistance mutations were defined by IAS-USA. Predicted phenotypes were calculated by the Stanford University database.
Results: Five hundred and fifty-eight patients were studied, of whom 394 (70.6%) had heterosexually acquired HIV and 377 (67.6%) were infected outside the UK. TDR testing was performed in 406 patients (72.8%). Thirteen of 392 viral resistance profiles (3.3%) showed genotypic TDR. There was no significant association between TDR and any demographic or risk factor or baseline CD4 count. In particular, rates of TDR were similar in white British (6/147, 4.1%) and black African (7/224, 3.1%) patients. The numbers of patients with TDR to individual drug classes were: nucleoside reverse transcriptase inhibitors, 2 (0.5%); non-nucleoside reverse transcriptase inhibitors, 7 (1.8%); and protease inhibitors, 4 (1.0%). No patients had multi-class resistance detected. Eleven patients (2.8%) were predicted to have significant phenotypic resistance to at least one drug.
Conclusions: In a large unselected UK cohort, with high coverage of TDR testing, the prevalence of TDR was low and is in accordance with recent data, showing a decrease in the prevalence of TDR in the UK. Differences in population mix did not appear to explain this low rate.
Keywords: HIV drug resistance/resistance mutations , antiretroviral therapy , knowledge/attitude/practice studies
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Introduction |
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Since 2005, the British HIV Association (BHIVA) has recommended testing for transmitted antiretroviral drug resistance (TDR) for all newly diagnosed patients.1 TDR prevalence has been reported for a range of HIV cohorts, predominantly from developed countries. Variation in rates of TDR between cohorts may be due to myriad factors, including definition of resistance, degree of selection of patients for testing and geographical setting. Overall, a TDR rate of 8% to 10% is frequently quoted for Western HIV cohorts. UK estimates include 7.1% and 14.2%.2,3 Anecdotally, the rate of TDR in our region seemed low. Our objectives were therefore to audit the current practice of TDR testing; to estimate the prevalence of TDR in our region; to describe the pattern of specific resistance mutations found; and to describe any associations with demographic or risk groups.
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Patients and methods |
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The present study was conducted as part of an audit of TDR testing across the Yorkshire and north-eastern regions of England. Eight centres participated, representing more than a half of all HIV care provided within the region. The local HIV prevalence (25–50 per 100 000 of general population) is typical of the UK, outside London and south-east England. All adult patients presenting with newly diagnosed HIV-1 infection in the 2 year period from March 2005 to March 2007 were included. All patients were therefore treatment-naive. Data were collected by reference to locally held databases and case note review by the investigators. The following demographic data were collected for each patient (based on history recorded from patients and reference to previous medical records): age, gender, ethnic group, likely route of HIV infection and likely country of infection. Baseline CD4 lymphocyte count and HIV viral load were recorded. If a patient was diagnosed during pregnancy, this was also recorded.
Genotypic resistance testing was performed by VircoType HIV-1 assay. Genotypic reports were submitted to a single investigator for analysis. Significance of mutations was defined using current IAS-USA lists.4 In addition, T215 revertants (T215C/D/E/I/S/V) were recorded. The predicted phenotype for each patient was calculated using the current Stanford University database (HIVdb program, http://hivdb.stanford.edu), and the predicted phenotypic intermediate or high-level resistance to any antiretroviral drug was recorded.
Statistical calculations were performed using SPSS 14.0.2. The proportion of patients in various subgroups was compared using 
2 test for binary variables and using binomial logistic regression for continuous exposure variables. Ninety-five percent confidence intervals (CIs) for proportion estimates were calculated using finite population corrections based on UK HPA data for all newly diagnosed cases of HIV in the region for 2005 and 2006.5
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Results |
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Five hundred and fifty-eight patients were included, of whom 293 (52.5%) were male. One hundred and ninety-nine patients (35.7%) described themselves to be of white British ethnicity and 326 (58.4%) black African. Mean age was 35 years (range 17–69). Most HIV infections were likely to have been acquired heterosexually (394, 70.6%) and outside the UK (377, 67.6%). Fifty-two patients (9.3%) were diagnosed during pregnancy. One hundred and ninety patients (34.1%) presented with CD4 lymphocyte count below 200 cells/mm3 (22.6% of white British and 40.2% of black African persons).
The overall rate of testing for TDR was 406 of 558 newly diagnosed patients (72.8%). Seven of the eight participating centres reported having a policy of universal TDR testing (i.e. in line with BHIVA guidance). At these seven centres, 387/503 patients (76.9%; range 56.0–89.7) actually had a TDR test recorded. Testing was performed in a greater proportion of men who have sex with men (MSM) (115/141, 81.6%) than in heterosexual persons (HTS) (278/394, 70.6%) and in a greater proportion of those likely to have acquired HIV infection in the UK (144/181, 79.6%) than outside the UK (262/377, 69.5%). The rate of testing did not vary with patient age or baseline CD4 count. Twenty-nine of the 52 newly diagnosed women presenting during pregnancy had TDR testing performed (55.8%).
Three hundred and ninety-two genotypic resistance profiles were analysed (in a further 14 tests, genetic material failed to amplify). The rate of genotypic TDR was 13 of 392 samples (3.3%, 95% CI: 1.9–4.7). No significant associations were found between the presence of TDR and any specific demographic factor or risk group (Table 1). TDR was detected in 6/147 white British patients (4.1%), compared with 7/224 black Africans (3.1%). Rates in MSM (4/108, 3.7%) and HTS (8/269, 3.0%) were also very similar. There was no association between age, baseline CD4 count or HIV viral load and the presence of TDR. No TDR was detected in the 27 samples from pregnant women.
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All patients with TDR had single-class resistance, usually with only one significant mutation detected. Seven patients had non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (1.8%), and two (0.5%) had thymidine analogue mutations. A further four patients (1.0%) had T215 revertants. Four patients had major protease inhibitor (PI) mutations (1.0%); in all cases, this was a single major PI mutation. Table 2 shows the specific mutations detected. Eleven of 392 patients (2.8%) had a genotype predicted to confer intermediate or high-level resistance to at least one antiretroviral drug.
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Discussion |
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We have described the rate of TDR testing and the prevalence of TDR detected in a diverse cohort in northern England. This represents one of the largest studies of TDR reported in a regional UK cohort. The uptake of TDR testing was reasonably high; however, there was a marked variation between units. Furthermore, testing was performed in a greater proportion of white British patients and MSM, compared with other groups. In some cases where TDR testing was not performed, clinicians may have made a subjective assessment that a patient was at low risk for TDR. This decision would have been supported by previously published data, which suggested that patients of British origin had an
10-fold higher rate of TDR than those of non-British origin.2 The rate of TDR we detected was 3.3%, which is among the lowest recently reported for a developed country. The direct comparison of TDR rates across studies is difficult, and such data can only provide a ‘snapshot’ of rates in a given population over a defined time period. Explanations for our low rate when compared with previously published data may conceivably include the following: degree of precision in the estimation of TDR rates; local demographic or transmission factors; and a reflection of a national trend in TDR rates.
Much historical TDR data were gathered at a time when testing was selective rather than universal.3 This may tend to have led to the overestimation of the rate of TDR in the underlying cohort. In our study, high uptake of testing, coupled with broad coverage within our region, means that our study should provide a good estimate of the local rate of TDR. Our population included a significant minority of late presenters with presumed long-standing HIV infection. This raises the possibility of reversion of TDR to wild-type virus over time, and hence, the detection of a lower rate of TDR. It remains controversial to what extent reversion occurs and the phenomenon differs between mutations.6,7 However, late presentation is unlikely to fully explain the low TDR rate, as there was no association between baseline CD4 count and TDR. Furthermore, the most strikingly low rate (compared with previous studies) was in white British patients, and late presenters were uncommon in this group.
Considering local factors, our cohort has a high proportion of black Africans (58.4%), compared with some studies. Non-British origin has previously been associated with markedly lower rates of TDR (1.4% compared with 15.8%).2 However, there was no such difference found in our population. The rate of TDR in our black African subgroup (3.1%) was higher than might have been expected, potentially suggesting increasing transmission of drug-resistant virus in sub-Saharan Africa. It is also possible that some of these patients may have had undisclosed prior antiretroviral exposure (including single-dose nevirapine). Clearly, this is one reason for performing TDR testing. Published data do suggest that TDR in the non-B subtype virus in Western Europe may be increasing, although, in this study, the rate in subtype B still remained markedly higher.8 Therefore, the low overall prevalence of TDR in our cohort particularly reflects lower than expected rates among white British MSM. Future research could investigate whether regional variations in sexual networks might explain differing rates of TDR in MSM. No studies to date have addressed this question in the UK; however, high-risk behaviour was not associated with TDR in a New York clinic.9 Our data do not therefore support a selective approach to TDR testing based on high-risk groups, as we did not identify any subgroup with significantly increased risk of TDR (Table 1).
Until recently, the prevalence of TDR in the UK had been increasing.3 We do not have historical TDR data specific to our region; however, over 1996–2003, the TDR rate for the UK outside London and south-east England was reported to be very high (18.2%).3 However, new UK-wide data have shown a peak rate of TDR of 14% in 2001–02, followed by a fall to 8% by the end of 2004.10 Our data may therefore reflect this trend.
All our centres use efavirenz with tenofovir or abacavir and lamivudine or emtricitabine in the treatment-naive patient, unless there are specific contraindications. This is in line with national guidance.1 Our patients, in whom TDR testing might be expected to change clinical management, are therefore those 8 (2.0%) with predicted NNRTI resistance. Based on our data, the developing technology of allele-specific limited TDR testing (for example, for RT K103N) could merit further exploration. It is worth noting, however, that the up-to-date prevalence of TDR cannot be known without accurate monitoring. This may be most easily achieved through ‘universal’ testing, although sentinel studies are another valid approach.
Our study has shown a low rate of TDR within a UK regional setting. This result is in keeping with recent national data reporting falling rates of TDR. However, the contribution of TDR acquired outside the UK was unexpectedly important and raises concerns for the future.
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Funding |
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No specific funding was received for this study.
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Transparency declarations |
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TopAbstractIntroductionPatients and methodsResultsDiscussionFundingTransparency declarationsReferences |
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None to declare.
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Acknowledgements |
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We thank David H. Dockrell, Babiker Elawad, Julia M. Greig, Hugh McGann, Paul McWhinney and Jane Minton.
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References |
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2
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3
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7 Pao D, Andrady U, Clarke J, et al. Long-term persistence of primary genotypic resistance after HIV-1 seroconversion. J AIDS (2004) 37:1570–3.[CrossRef]
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9 Kozal MJ, Amico KR, Chiarella J, et al. Antiretroviral resistance and high-risk transmission behaviour among HIV-positive patients in clinical care. AIDS (2004) 18:2185–9.[CrossRef][Web of Science][Medline]
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