JAIDS Journal of Acquired Immune Deficiency Syndromes:
A Randomized Controlled Trial of the Value of Phenotypic Testing in Addition to Genotypic Testing for HIV Drug Resistance: Evaluation of Resistance Assays (ERA) Trial Investigators
Received for publication July 7, 2004; accepted October 11, 2004.
Supported by the National Health Service (NHS) London Regional Office, Research and Development Programme.
The views expressed in the publication are those of the authors and not necessarily those of the NHS or the Department of Health.
Reprints: David Dunn, HIV Division, Medical Research Council Clinical Trials Unit, 222 Euston Road, London NW1 2DA, United Kingdom (e-mail: firstname.lastname@example.org).
Objectives: To assess the clinical utility of phenotypic resistance testing in addition to genotypic resistance testing among HIV-1-infected patients experiencing virologic failure and with limited therapeutic options.
Design: Multicenter randomized trial.
Methods: Patients were eligible if a decision had been made to switch antiretroviral therapy, the most recent HIV-1 RNA plasma viral load (VL) exceeded 2000 copies/mL, and the clinician was unable to select a potent regimen of 3 or more drugs without access to a resistance test. Subjects were randomized to genotypic resistance testing alone (G arm) or to genotypic plus phenotypic testing (G + P arm). Patients had access to resistance testing at any time during follow-up (minimum of 1 year) according to the original allocation. The primary end point was change in plasma VL from baseline at 12 months.
Results: Three hundred eleven patients were recruited between February 2000 and July 2001. At baseline, mean VL and CD4 count were 4.23 log10 copies/mL and 275 cells/mm3, respectively, and subjects had previous exposure to a mean of 7.7 antiretroviral drugs. There was no appreciable difference between the study arms in the drug regimens prescribed after randomization. Mean reduction in VL load at 12 months was similar in the 2 arms (G: 1.37 log10 reduction, G + P: 1.28 log10 reduction; P = 0.77), as was the proportion of subjects with VL <50 copies/mL (G: 35%, G + P: 27%).
Conclusion: The study did not demonstrate added value of phenotypic resistance testing in conjunction with genotypic resistance testing in patients with limited therapeutic options.
HIV drug resistance can be assessed by a genotypic test, which detects relevant mutations in the protease and reverse transcriptase genes, or by a phenotypic test, which estimates the fold increase in drug concentration required to achieve the same degree of viral inhibition compared with a wild-type strain. Of these 2 methods, a phenotypic test gives a more direct quantitative measure of resistance, which avoids the difficulty of mutational interpretation. Conversely, sensitivity cutoffs need to be defined, and the test is more expensive, has a slower turnaround time, and is less widely available.1-4
Numerous randomized trials have assessed the effect of genotypic testing5-10 or phenotypic testing7,11-13 on short-term virologic response using a no-test group as a comparator. Despite the conflicting results generated by these studies as well as some methodologic concerns,14 clinical guidelines concur that resistance testing should be used for all patients experiencing treatment failure for whom treatment change is being considered.1-4 Guidance on the choice between genotypic and phenotypic testing is less prescriptive, partly because of the limited randomized evidence on this issue. Despite a lack of clear supportive data, 1 group recommended that “for patients with a complex treatment history…both assays might provide critical and complementary information”.4
The Evaluation of Resistance Assays (ERA) trial was a 2-part, multicenter, randomized trial that enrolled patients at therapeutic failure. This article focuses on the results of part B, which included patients who, in general, were highly treatment experienced. All subjects in this part had access to genotypic resistance testing throughout the study (minimum of 1 year of follow-up) and were randomized in addition to have or not have access to phenotypic testing. This addresses the question of the added value of phenotypic resistance testing in conjunction with genotypic resistance testing.
HIV-1-infected patients aged 18 years or older were enrolled from 26 clinical centers in the United Kingdom. Patients were eligible if a decision had been made to switch antiretroviral therapy as a consequence of virologic failure, provided that the most recent HIV-1 RNA plasma viral load (VL) exceeded 2000 copies/mL. Part B included patients if the clinician perceived that he or she was unable to select a potent regimen of 3 or more drugs without using a resistance test (part A, which is to be reported elsewhere, included the converse and compared genotypic testing with standard of care). Patients were ineligible if they were naive to antiretroviral drugs or had previous exposure to 1 or 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) only, if a phenotypic resistance test had previously been performed, if they were unlikely to comply with a routine schedule of visits, or if they had a life expectancy of less than 12 months.
Randomization was performed centrally using a random number generator stratified by center. Patients had access to resistance testing at subsequent treatment failures according to the original allocation. For patients in whom the test was unsuccessful, the clinician could opt to repeat the test with a new blood sample or to change treatment without the benefit of a resistance report. Follow-up was carried out according to the routine schedule used at each center and was continued for 12 months after the last recruitment. Expert advice on the interpretation of the resistance test or on the new antiretroviral regimen was not part of the study protocol, although the virologists on the ERA Steering Committee could be consulted on an individual case basis; however, this option was infrequently invoked.
Resistance testing was performed by VIRCO (Mechelen, Belgium). The phenotypic test (Antivirogram, version 2.0.00) reports the actual fold resistance for each drug (ie, the ratio of the 50% inhibitory drug concentration [IC50] for the test sample relative to a reference virus)15; this result was classified as “sensitive” (≤4-fold), “intermediate” (4-10-fold), or “resistant” (>10-fold). The genotypic test (VircoGEN) showed key drug-associated mutations and classified each drug as “no evidence of resistance,” “resistance possible,” or “evidence of resistance” using a rules-based interpretation. In commercial operations, VIRCO introduced modified tests in January 2001, but to avoid unduly complicating the interpretation of the ERA trial, these new tests were not used in the trial until recruitment had closed (ie, only for the last 12 months of follow-up). The main changes to the tests were: (1) for the genotypic test, replacement of a rules-based interpretation system with the predicted fold change in phenotypic resistance based on approximate matches in a genotype-phenotype database (VirtualPhenotype); (2) use of single cutoff values for drug susceptibility that reflect the normal range for wild-type strains (“biologic cutoff value”); and (3) addition of lopinavir to both reports.
The primary endpoint was change in plasma HIV-1 RNA VL between baseline (date of randomization) and 12 months. VL measurements at baseline and 12 months were performed centrally, blinded to randomized group, using Roche Amplicor 1.5 (400-copy assay at baseline, 50-copy assay at 12 months). When a 12-month sample was not available within the permitted window of ±8 weeks, a local VL result was used in its place (n = 54), based on Chiron 3.0 (n = 34), Roche Amplicor 1.5 (n = 19), and nucleic acid sequence based amplification assay (NASBA) (n = 1). The main reasons for failure to achieve a centralized result were irregular patient attendance, failure to take a sample at the appropriate time, inability to locate samples, and patient death. Secondary end points included the proportion of patients with an undetectable VL (<50 copies/mL) at 12 months, change in locally measured plasma HIV-1 RNA VL and CD4 cell count, and antiretroviral treatment prescribed after randomization.
Sample Size and Statistical Analysis
It was initially estimated that a total of 240 patients (120 per arm) would give 90% power to detect (at a significance level of 5%) a difference in mean VL of 0.3 log10 copies/mL. This calculation overlooked the reduction in power as a result of test failures, however, and the sample size was consequently increased to 320 patients. All analyses were performed on an “as randomized” (intention-to-treat) basis, with time measured from the date of randomization. Data were not imputed for missing observations, except for HIV-related deaths, where a value of 100,000 copies was assumed (upper limit of detection by Roche Amplicor 1.5 Ultrasensitive assay). VL values were log10 transformed before analysis, and normal “interval” regression was used to account for VL values less than the lower limit or greater than the upper limit of the test.16
Three hundred eleven patients were recruited to part B of the study between February 2000 and July 2001: 152 to the genotypic resistance testing alone (G) arm and 159 to the genotypic plus phenotypic testing arm (G + P) arm. Baseline characteristics were reasonably well balanced between the 2 groups (Table 1). Overall, 39% of subjects had had a previous genotypic resistance test. Mean CD4 count and VL were 275 cells/mm3 and 4.2 log10 copies/mL, respectively; 73 (23%) subjects had a VL greater than 100,000 copies/mL. In general, subjects were highly treatment experienced; 79% had previous exposure to all 3 main drug classes and had received a mean of 7.7 different antiretroviral drugs over a mean period of 49 months. This was reflected in a high frequency of drug-associated mutations: among the 259 samples successfully genotyped, 80%, 68%, and 44% had 1 or more primary NRTI-, nonnucleoside reverse transcriptase inhibitor (NNRTI)-, and protease inhibitor (PI)-associated mutations, respectively. Resistance to 2 or more classes was common, with 13% of samples showing evidence of resistance to NRTIs and PIs, 29% to NRTIs and NNRTIs, and 29% to all 3 classes; 8% of samples had no primary mutations. Another angle on the extent of preexisting resistance is the number of drugs to which the resistance test indicates reduced sensitivity. Using the genotypic test, because this was employed in both groups, 48% of viral samples showed some resistance to between 5 and 9 drugs and 30% showed resistance to 10 or more drugs.
Resistance Tests at Baseline
The median interval between collection of the blood sample at randomization and communication of the resistance report to the clinician (by e-mail and/or telefax) was 20 (range: 8-39) days in the G group compared with 29 (range: 10-47) days in the G + P group, including the time for transport of the specimens (median of 7 days). In the G + P group, the genotypic and phenotypic reports were sent at the same time, even though the genotypic test has a shorter turnaround time, to encourage the use of both reports in treatment decisions. Including any repeat tests, 138 (91%) patients in the G group had a successful test. In the G + P group, a genotypic and phenotypic report was generated for only 123 (78%) patients, although another 13 (8%) subjects received a phenotypic report only and 13 (8%) received a genotypic report only. The probability of test failure was strongly related to VL but not to the patients' ethnicity (data not shown).
Discordance between the genotypic and phenotypic test results was arbitrarily defined as a different value on the 3-point susceptibility scale used for both tests, bearing in mind that the correspondence between the scales is not exact (see Methods section). Based on the baseline samples in the G + P arm, for which a phenotypic report and a genotypic report were generated, the discordance rate varied from 6% to 46% depending on the individual drug (Fig. 1). The highest levels of discordance were observed in the NRTI class, particularly for zalcitabine (46%), zidovudine (42%), abacavir (40%), and didanosine (38%), although indinavir (44%) was also problematic. Apart from zidovudine and efavirenz, most cases of discordance were a result of the genotypic test indicating a higher level of resistance than the phenotypic test.
Treatment Regimens Prescribed After Randomization
Six subjects (3 in the G arm, 3 in the G + P arm) changed drug regimen before the result of the resistance test became available. In the G arm, the proportion of subjects who had started a new regimen was 46% at 8 weeks, 70% at 16 weeks, and 77% at 24 weeks; the corresponding figures in the G + P arm were slightly lower at 39%, 65%, and 73%. The reasons for not switching or delayed switching of a regimen were not elicited but may have included the test(s) indicating no clear benefit of switching drugs, the drugs to which the virus was susceptible being unacceptable to clinicians and/or patients, or irregular clinic attendance.
There were no significant differences between the randomized groups in terms of the drug classes prescribed, number of drugs in the new regimen, or number of drugs that were continued from the previous regimen or recycled (Table 2). Also, the frequency of use of specific antiretroviral drugs did not seem to be influenced by the addition of the phenotypic test (Fig. 2). Notably, lopinavir/ritonavir was included in 51% of new regimens despite not being included in the resistance reports (genotypic or phenotypic) at trial entry.
Resistance Tests and Changes in Antiretroviral Regimen After Baseline
A total of 133 postbaseline resistance tests were performed over 535 person-years of follow-up (25 tests per 100 person-years). There were a total of 137 second or subsequent changes in antiretroviral therapy over 411 person-years of observation (33 per 100 person-years), defined as the introduction of 2 or more new drugs subsequent to the initial treatment change after randomization. Fifty-two (18%) subjects changed therapy for a second time before 12 months. Of interest, only 30% of second or subsequent treatment changes were preceded by a resistance test. Findings were similar for the 2 randomized groups in all these analyses (data not shown).
Virologic, Immunologic, and Clinical End Points
The primary end point, reduction in VL between baseline and 12 months, was recorded for 136 (89%) subjects in the G group and 147 (92%) in the G + P group. This included 9 patients who died of an HIV-related cause before 12 months (6 in the G arm, 3 in the G + P arm), who were assigned a notional VL of 100,000 copies/mL (see Methods section). The mean (SE) reduction in VL between baseline and 12 months was 1.37 (0.20) log10 copies/mL in the G arm compared with 1.28 (0.19) in the G + P arm, a difference of 0.08 (95% confidence interval [CI]: −0.46 to 0.62; P = 0.8). A comparison of the proportion of subjects with a VL of <50 copies at 12 months also failed to reveal a significant difference between the groups (G arm: 48 [35%] of 136 patients, G + P arm: 40 [27%] of 147 patients; P = 0.3).
Figure 3a shows changes in VL measured locally at 3-month time points. This seems to show a leveling off in the G group after 9 months, whereas the mean VL in the G + P group continues to decline to at least 18 months. None of the differences at individual time points are statistically significant, however, nor was a global test allowing for repeated measurements based on all values at or after 12 months (P = 0.3). Both groups showed steady but similar rises in CD4 cell count, with average gains of 36 cells/mm3 by 12 months and 63 cells/mm3 by 18 months (see Fig. 3b). This improvement in an advanced patient population suggests that the decision to switch antiretroviral therapy at that point in time was, in general, an appropriate one.
It has been conjectured that resistance testing may be of less benefit in patients with extensive prior exposure to antiretroviral drugs.7,8 We examined this question by repeating the primary end point analysis, stratifying subjects by whether they had received a cumulative total of fewer or more than 8 drugs at trial entry. The difference between the G and G + P groups was similar in the 2 strata (<8 drugs: 0.09 greater reduction in log10 [VL] in the G group, ≥8 drugs: 0.07 greater reduction in log10 [VL] in the G group). Similar analyses based on the number of drug classes previously exposed to and the number of drugs to which the baseline genotypic report indicated resistance also showed no evidence of statistical interaction.
A total of 18 deaths were observed (13 classified as probably or definitely HIV related), 11(7 classified as probably or definitely HIV related) in the G group and 7 (6 classified as probably or definitely HIV related) in the G + P group. During the study, there were 16 and 13 new AIDS-defining events in the G and G + P arms, respectively, all of which occurred in patients who had had an AIDS diagnosis before trial entry.
To date, 3 other trials have performed a “head-to-head” comparison of the 2 modes of resistance testing.7,17,18 The GenPheRex trial randomized 201 patients to therapy guided by a VirtualPhenotype or phenotypic test result at the point of treatment failure.17 At the end of follow-up (48 weeks), virologic response was similar in both groups whether assessed by VL reduction or by the likelihood of achieving a VL load less than 400 copies/mL. Interpretation is complicated by the facts that many patients (53%) switched therapy for a second time before 48 weeks and the use of repeat resistance testing is not described. Using a similar design, the Realvirfen study randomized 300 patients (276 analyzed) to phenotypic testing or a locally performed genotypic test that was submitted for VirtualPhenotype analysis.18 Fifty-six percent of subjects in the genotypic arm and 47% in the phenotypic arm achieved a VL <400 copies/mL at week 24 (P = 0.1); the corresponding mean reductions in VL from baseline were 1.0 and 1.3 log10 copies (P = 0.02). A third trial suggested, albeit inconclusively, that genotypic testing might be superior to phenotypic testing. The NARVAL (ANRS 088) randomized 541 patients to genotyping, phenotyping, or no testing.7 The proportion of patients fulfilling the primary endpoint (VL <200 copies/mL at week 12) was higher in the genotypic arm (44%) than in the phenotypic arm (35%), a difference bordering on statistical significance (P = 0.08). This difference narrowed with longer follow-up, however; surprisingly, there was no effect on VL reduction at any time point. None of these 3 studies found any impact of the method of resistance testing on CD4 cell count changes.
The ERA trial showed no substantive differences between genotypic testing alone and the combined use of genotypic and phenotypic testing in virologic or immunologic response. The G group achieved a slightly greater reduction in VL at 12 months, by an average of 0.08 log10 copies/mL. The 95% CI for this difference is wide, however, with the data being compatible with up to a 0.62 log10 advantage for genotypic testing alone or up to a 0.46 log10 advantage for combined testing. Thus, the lack of statistical significance should not be interpreted as proof of “equivalence” of these 2 strategies of testing. Also, a planned cost-effectiveness analysis was not carried out because of the lack of a clear benefit of the intervention. Based on routine local VL measurements, there was some suggestion that combined testing conferred a delayed virologic advantage, but there is no obvious plausible explanation for this observation. The power of the study was reduced by resistance test failures and patients delaying or not changing therapy after the test. These are natural facets of resistance testing, however, and the intention-to-treat analysis presented is the most valid approach for assessing the impact of different resistance testing policies.19
The negative findings in some trials of resistance testing have been attributed to a high proportion of heavily pretreated subjects, because it is likely that many such patients have archived resistance or cross-resistance to most, it not all, available antiretroviral drugs. As in related studies,7,17,18 most patients in ERA trial had complex treatment histories; on average, therapy had been received for 48 months and a total of different 7.7 drugs had been prescribed. Repeating the main comparisons stratified by prior drug history failed to identify any particular subgroup that gained benefit from the addition of phenotypic testing, however.
The clinical effect of resistance testing is mediated through its influence on the selection of drug regimens and examination of this “process variable” is key in the interpretation of randomized trials. In this study, the additional information provided by phenotypic tests had no appreciable effect on the number of drugs used, the extent to which drugs were recycled, or the specific drugs that were prescribed. Notably, just more than half of the subjects were prescribed lopinavir/ritonavir, which was available only through an open access program during the period of recruitment to the study. Because lopinavir did not appear on the resistance reports used at study entry (see Methods section) and the relative effect of different protease mutations on its susceptibility are still incompletely understood,20 this drug was presumably prescribed on the basis of its high genetic barrier to resistance. This highlights the need for frequent modification of phenotypic tests and refinement of genotypic algorithms to keep abreast of new drug development. It also reveals the inherent limitations of randomized studies of resistance testing in highly drug-experienced patients, because there is always a tendency to use newly available drugs in all arms.
The similarity in the drug regimens prescribed in the 2 groups was perhaps surprising in light of the level of discordance between the genotypic and phenotypic test results. Parkin and colleagues21 have described multiple possible reasons for genotype/phenotype discrepancy, including limitations of current genotypic interpretation algorithms (particularly in the case of complex mutational patterns), difference in test sensitivity as a result of amino acid mixtures, and the choice of phenotypic cutoffs used to designate susceptibility or resistance. In line with this and other studies,17,18 we found that levels of discordance were generally higher among drugs in the NRTI class and that a genotypic test result tended to indicate a higher level of resistance than a phenotypic test result. An important difference between the ERA trial and the NARVAL, GenPheRex, and Realvirfen trials was the provision of a phenotypic test in addition to rather than instead of a genotypic report. The ERA trial did not attempt to measure the relative influence of the 2 test results (in the G + P group) on prescribing decisions. The similarity between the randomized groups suggests that clinicians may have acted conservatively and placed greater emphasis on the genotypic test result, however. Alternatively, prescribing decisions may have been dictated by independent factors such as drug tolerability or the desire to use novel drugs. In a recent experiment, 13 experts were asked to recommend antiretroviral regimens for 5 patients based on a genotypic test alone, a phenotypic test alone, or the 2 tests in combination.22 In pairwise comparisons, differences in regimens were smallest between the second and third groups, suggesting a greater import of the results of the phenotypic tests than of the genotypic tests. Although it may be correct that the 2 types of test provide “complementary” information,4,21 the results of the ERA trial lead us to question whether this necessarily translates to the selection of more optimal antiretroviral regimens.
It is inherently difficult to assess diagnostic tests in a rapidly moving field, and the results of this study largely reflect the effect of tests that have been superseded.23 Nevertheless, in the case of the phenotypic test, the intervention essentially evaluated by part B of the ERA trial, the only change was in the interpretation of the fold resistance values and not the values themselves. Also, the changes in the genotypic test meant it became more similar to the phenotypic test so that, logically, a trial conducted now would be seeking to detect even smaller differences. In conclusion, the ERA trial found no clear evidence of an added benefit of phenotypic resistance testing in conjunction with genotypic resistance testing, but caution should be exercised in generalizing this finding.
VIRCO (Mechelen, Belgium) provided resistance testing and transport of plasma samples to Belgium. The International Clinical Virology Centre performed VL measurements on the baseline and 12-month samples.
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10. Wegner SA, Wallace M, Aronson A, et al. Evaluation of the clinical efficacy of antiretroviral resistance testing (CERT) [abstract ThOrB1389]. Presented at: XIV International AIDS Conference; 2002; Barcelona.
11. Melnick D, Rosenthal J, Cameron M, et al. Impact of phenotypic antiretroviral drug resistance testing on the response to salvage antiretroviral therapy (ART) in heavily experienced patients [abstract 786]. Presented at: Seventh Conference on Retroviruses and Opportunistic Infections; 2000; San Francisco.
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13. Haubrich R, Keiser P, Kemper C, et al. CCTG 575: a randomized, prospective study of phenotype testing versus standard of care for patients failing antiretroviral therapy [abstract 80]. Presented at: Fifth International Workshop on HIV Drug Resistance and Treatment Strategies; 2001; Scottsdale, AZ.
14. Dunn DT, Gibb DM, Babiker AG, et al. HIV drug resistance testing: is the evidence really there? Antivir Ther
15. Hertogs K, de Bethune MP, Miller V, et al. A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs. Antimicrob Agents Chemother
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(GenPheRex) Trial. J Acquir Immune Defic Syndr
18. Perez-Elias MJ, Garcia-Arata I, Muñoz V, et al, for the Realvirfen Study Group. Phenotype or virtual phenotype for choosing antiretroviral therapy after failure: a prospective, randomized study. Antivir Ther
19. Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutic trials. J Chronic Dis
20. Parkin NT, Chappey C, Petropoulos CJ. Relationship between lopinavir (LPV) susceptibility and HIV-1 protease genotype [abstract 581]. Presented at: Ninth Conference on Retroviruses and Opportunistic Infections; 2002; Seattle.
21. Parkin N, Chappey C, Maroldo L, et al. Phenotypic and genotypic HIV-1 drug resistance assays provide complementary information. J Acquir Immune Defic Syndr
22. Zolopa AR, Bates M, Parkin N. Experts select different antiretroviral regimens when presented with resistance data in the form of genotype, phenotype, or combined genotype plus phenotype. Antivir Ther
23. Dunn DT, McCormack S, Babiker A, et al. Tracker trials. BMJ
A. G. Babiker, A. Breckenridge (Chairman), J. H. Darbyshire, D. T. Dunn, A. Fakoya, M. Fisher, A. Leigh Brown, C. Loveday (Principal Investigator), S. McCormack, D. Pillay, A. Poppa, A. Rinehart, W. Verbiest, and I. Williams
D. T. Dunn, H. Green, C. Loveday, A. Rinehart, D. Pillay, M. Fisher, S. McCormack, A. G. Babiker, and J. H. Darbyshire
Data and Safety Monitoring Committee
A. McLaren, P. Armitage, V. Beral, and H. Lambert
Medical Research Council Clinical Trials Unit
A. G. Babiker, D. T. Dunn, H. Green, P. Kelleher, S. Khan, S. McCormack, and F. Tyrer
W. Verbiest, A. Rinehart, L. Bacheler, P. McKenna, K. V. Bonduelle, P. Schel, C. Jordens, A. Ghys, and M. Van Brandt
Royal Free and International Clinical Virology Centre
C. Loveday, J. Page, J.-L. Faudon, and K. Jones
Participating Clinical Centers
Barts and the Royal London Hospital, London (M. Murphy, G. Roper, P. Davis, J. Norman, and P. Sashi), Central Middlesex Hospital, London (R. Fox, L. McDonald, and B. Patel), Chesterfield and North Derbyshire Royal Hospital, Chesterfield (K. Rogstad and B. Purdon), Doncaster Royal Infirmary, Doncaster (J. Hawkswell and G. Ball), Edinburgh Western General, Edinburgh (C. Leen, S. Morris, C. Wilson, and S. Burns), Essex County Hospital, Colchester (S. Jebakumar), Gartnavel General Hospital, Glasgow (R. Fox, S. Eves, S. Cameron, and J. McCowan), Kings College Hospital, London (P. Easterbrook, C. Taylor, A. Waters, D. Graham, and L. McQueen), Leeds General Infirmary, Leeds (E. Monteiro and G. Booth), Leicester Royal Infirmary, Leicester (M. Wiselka, J. Laurenti, S. Bonnington, and S. Sikotra), Mayday University Hospital, Croydon (M. Rodgers, T. Newell, and P. Riley), Middlesbrough General Hospital, Middlesbrough (B. McCarron, L. Lowery, and J. Bashford), Mortimer Market Center, London (I. Williams, D. Cornforth, D. Aldam, E. MacFarlane, and S. Rice), Newcastle General Hospital, Newcastle (E. Ong, M. Snow, A. Harrison, A. Turner, and A. Rudsdale), Newham General Hospital, London (A. Fakoya and C. Tawana), North Manchester General Hospital, Manchester and St. Thomas's Hospital, Stockport (E. Wilkins, R. Daintith, E. Stockwell, and A. Bailey), North Middlesex Hospital, London (J. Ainsworth and L. DuRibbo), Royal Berkshire Hospital, Reading (R. Manoharan, D. Nelson, and J. Selwood), Royal Free Hospital, London (M. Johnson, M. Tyrer, D. Wilson, T. Drinkwater, Z. Cuthbertson, P. Bryne, F. Turner, and C. Loveday), Royal Bolton Hospital, Manchester (S. Ahmad and E. Morgan), Royal Hallamshire Hospital, Sheffield (C. Bradbury, S. Herman, D. Docrall, C. Care, and G. Ball), Royal Sussex County Hospital, Brighton (M. Fisher, D. Churchill, N. Perry, J. McIntosh Roffey, and A. McCue), St. George's Hospital, London (F. Davidson, P. Hay, A. Adebiyi, M. Ogunfile, M. Wansbrough-Jones, and B. Edwards), St. Thomas's Hospital, London (B. Peters, L. Judges, N. Saint, J. Turpitt, A. Ronald, L. Burghard, and S. O'Shea), Queen Elizabeth Hospital, Woolwich (J. Russell, S. Mitchell, and G. Vosper), and Whittal Street Clinic, Birmingham (M. Shamanesh and G. Gilleran)
drug resistance testing; genotypic testing; phenotypic testing; randomized trial
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