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Effect of HIV-1 Subtype on Virologic and Immunologic Response to Starting Highly Active Antiretroviral Therapy

  1. Anna Maria Geretti1,2,
  2. Linda Harrison4,
  3. Hannah Green4,
  4. Caroline Sabin3,
  5. Teresa Hill3,
  6. Esther Fearnhill4,
  7. Deenan Pillay2,5,
  8. David Dunn4, and
  9. on behalf of the UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Studya
  1. 1Royal Free Hampstead NHS Trust, London, England
  2. 2Departments of Virology, London, England
  3. 3Departments of Primary Care and Population Sciences, University College London Medical School, London, England
  4. 4Departments of Medical Research Council Clinical Trial Unit, London, England
  5. 5Departments of Specialist and Reference Microbiology Division, Health Protection Agency, London, England
  1. Reprints or correspondence: Dr. Anna Maria Geretti, Royal Free Hampstead NHS Trust and University College London Medical School, Pond St. London NW3 2QG, England (a.geretti{at}medsch.ucl.ac.uk).
 
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Abstract

Background. It has been proposed that subtype-related human immunodeficiency virus type 1 (HIV-1) variability may influence virologic and immunologic responses to highly active antiretroviral therapy (HAART). Studies to date, however, have described treatment outcomes predominantly in persons with subtype B infection or compared subtype B with diverse non-B subtypes grouped together.

Methods. With use of data from the linked UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study databases, time to viral load undetectability (viral load, <50 copies/mL), time to virologic rebound (viral load, >1000 copies/mL), and increases in the CD4 cell count were compared for a median of 39 months (interquartile range, 23–67 months) in drug-naive patients infected with subtype B (n=1550), subtype C (n=272), subtype A (n=66), circulating recombinant form AG (n=57), or subtype D (n=41) disease who started HAART.

Results. Overall, 1906 (90%) of 2116 patients achieved viral load undetectability within 12 months after they started HAART, of whom 335 (18%) subsequently experienced virologic rebound. In adjusted analyses, viral load suppression occurred more rapidly in patients infected with subtype C (hazard ratio, 1.16; 95% confidence interval, 1.01–1.33; P=.04) and subtype A (hazard ratio, 1.35; 95% confidence interval, 1.04–1.74; P=.02) relative to subtype B infection. The virologic rebound occurred marginally more rapidly in patients with subtype C infection (hazard ratio, 1.40; 95% confidence interval, 1.00–1.95; P=.05), but the hazard of virologic rebound was similar with other subtypes. Although persons with subtype B infection showed higher baseline CD4 cell counts and maintained the advantage throughout therapy, CD4 cell count recovery occurred at similar rates with all subtypes.

Conclusions. Patients infected with prevalent non-B subtypes were as likely to achieve viral load suppression as persons infected with subtype B and showed comparable rates of CD4 cell count recovery. HAART achieves excellent outcomes regardless of the infecting subtype.

Subtype B infection has for many years dominated the HIV-1 epidemic in Western Europe and continues to account for most infections in North America [1]. As a result, clinical trials and observational cohorts to date have analyzed the efficacy of HAART, predominantly in patients with subtype B infection. On a global scale, however, subtype B infection causes just more than 12% of infections, whereas subtype C infection accounts for ∼48%. The prevalence of non-B subtypes has been increasing in Western Europe in recent years through immigration from sub-Saharan Africa, Asia, and Eastern Europe. Multiple HIV-1 strains cocirculate [2–5], although parallel epidemics are commonly observed whereby subtypes segregate according to ethnicity and transmission group. Thus, infection with subtype B occurs predominantly among white men who have sex with men and injection drug users, whereas non-B subtypes predominate in heterosexual men and women of other ethnic groups.

HIV-1 subtypes differ in their structural, regulatory, and accessory genes, long terminal repeat sequences, transcriptional promoters, and response to transcriptional factors. These differences may influence cellular tropism and kinetics of viral replication and modulate disease progression [6] and susceptibility to antiretroviral drugs [7, 8]. When comparing subtype B with common non-B subtypes and circulating recombinant forms (CRFs), approximately one-half of reverse-transcriptase and protease codons are polymorphic in >1% of untreated patients [9]. Certain polymorphisms may reduce drug susceptibility, whereas others may facilitate the emergence of major drug resistance mutations during therapy [10, 11]. In vitro, some non-B subtypes show reduced susceptibility to antiretrovirals, such as abacavir, the nonnucleoside reverse-transcriptase inhibitors, and the protease inhibitors nelfinavir, atazanavir, and lopinavir [12, 13]. However, the effects are small, have not been consistently reproduced [14], and have uncertain clinical relevance.

Previous studies have analyzed virologic and immunologic responses to antiretroviral therapy according to the HIV-1 subtype [15–20]. All have the important limitation of comparing subtype B with non-B subtypes grouped together, a necessary oversimplification when dealing with small numbers of patients infected with non-B subtypes. The aim of this study was to assess virologic and immunologic responses to starting HAART in a large cohort, with the specific objective of comparing outcomes in patients with subtype B infection and those with subtype C, subtype A, CRF_AG, and subtype D infection, the predominant non-B strains circulating in the United Kingdom [4, 5].

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Methods

Study population. The reverse-transcriptase and protease nucleotide sequences were retrieved from the UK HIV Drug Resistance Database, which collates nearly all genotypic resistance tests conducted as part of routine care in the United Kingdom [21]. Demographic and clinical data were obtained via linkage to the UK Collaborative HIV Cohort Study [22, 23]. Analyses were performed with ethics committee approval. Eligible patients were aged >16 years, started first-line therapy in 1996–2006 with ⩾3 drugs, had a baseline resistance test from which the subtype was determined using the Rega genotyping tool, underwent baseline viral load and CD4 cell count measurement 3 months before to 1 week after HAART initiation, and had ⩾12 months of follow-up. Patients with a resistance test performed only after HAART initiation were not included, because the test would most likely have been performed because of previous failure, thus introducing bias. Other exclusion criteria were a baseline viral load <50 copies/mL, because an undetectable viral load in an untreated person may indicate an erroneous record, and intermediate-level to high-level resistance to any drug in the initial regimen, to limit the effects of transmitted drug resistance on treatment responses. Analysis assumed intention to continue treatment and did not consider treatment changes after starting HAART.

Statistical analysis. Baseline characteristics were analyzed using the χ2 test for categorical variables and analysis of variance for continuous variables. Kaplan-Meier and Cox regression analyses were used to assess differences in time from HAART initiation to viral load undetectability (viral load, <50 copies/mL), considered to occur at the midpoint between the last detectable and first undetectable measurement. Of 32,041 viral load measurements, 159 were reported using a lower limit of detection of <50 copies/mL (typically <400 copies/mL); they were considered to be detectable between 50 copies/mL and this limit. Among patients who achieved undetectability within 12 months of starting HAART, we assessed time from undetectability to virologic rebound. Virologic rebound was defined as 2 consecutive viral load measurements >1000 copies/mL or 1 measurement >1000 copies/mL followed by a treatment change and was considered to occur at the midpoint between the last measurement <1000 copies/mL and the first measurement >1000 copies/mL. A treatment change was defined as a change in ⩾3 drugs or in 2 drugs plus drug class. Patients were censored at their last recorded viral load. Because these analyses are sensitive to the timing of viral load measurement, we examined whether the time to the first measurement and time between subsequent measurements varied by subtype.

Multivariate analysis adjusted for age, clinical center of care, initial treatment regimen, calendar year of starting HAART, baseline CD4 cell count and viral load, and, in the virologic rebound analysis, time to viral load undetectability. Because of a strong association with subtype, adjustment was not possible for ethnicity and transmission group. Instead, the analysis was repeated to look separately at the effects of ethnicity and transmission group. Statistical power to detect true interactions between subtype and other covariates in the multivariate models was limited, and therefore tests for interactions were not undertaken. A sensitivity analysis was performed ignoring virologic rebounds during treatment interruption or when the viral load at virologic rebound was within 0.5 log10 copies/mL of the baseline viral load, the latter possibly reflecting nonadherence. Predicted times, from the multivariate Cox regression analyses, until a certain percentage of patients had an event were calculated. The difference in the rate of any drug change during follow-up was tested using Poisson regression.

Longitudinal mixed normal models [24] were used to assess the effect of subtype on changes in CD4 cell count over time, adjusting for the fact that the same patients were observed repeatedly. Because of the sharp increase in CD4 cell count in the first 3 months after starting HAART, only measurements after 3 months were included; a linear increase in the square root of the CD4 cell count was assumed. The initial CD4 cell count was used to adjust for differences at HAART initiation. Random effects allowed both the CD4 cell count at 3 months and subsequent increases in CD4 cell count to vary across patients. Multivariate analysis adjusted for main effects of potential confounders. Confounders were selected to have an additional effect on the increase in CD4 cell count over time (interactions with time) using backwards elimination. All analysis used Stata statistical software, version 10.0 (StataCorp).

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Results

Study population at HAART initiation. The characteristics of the 2116 patients stratified by HIV-1 subtype are given in table 1. The predominant strains comprised subtype B (73%), subtype C (13%), subtype A (3%), CRF_AG (3%), and subtype D (2%); these were analyzed individually. A diverse group of other non-B strains was detected (6%), including CRF_AE (21), subtype G (19), subtype F (1), subtype H (1), subtype J (1), complex CRFs (14), and unclassifiable strains (73).

Ethnicity and transmission group were strongly associated with subtype (P<.001 for both). Among patients with subtype B infection, 1335 (86%) were white and 1396 (90%) were men who have sex with men, compared with 35 (13%) and 11 (4%) patients with subtype C infection, respectively. Conversely, patients with subtype C infection were predominantly black African (206 patients [76%]) and heterosexual (237 patients [87%]). The most popular initial backbone was zidovudine and lamivudine (829 patients [39%]); most patients (1126 [53%]) took efavirenz as their third drug. Efavirenz was more commonly used by patients with subtype B infection (863 patients [56%]) than by those with other subtypes (P=.001), a difference driven by confounding by sex. Age and baseline CD4 cell count and viral load were higher in patients with subtype B infection compared with other patients (P<.001 for all). In addition, a larger proportion of patients with subtype B infection started HAART in earlier calendar years (1996–2000) (P<.001).

Time to viral load undetectability. Median follow-up time was 39 months (interquartile range, 23–67 months). The median time to the first viral load measurement after starting HAART (0.9 month) and the median intervals between subsequent viral load measurements (2.6 months) were the same for all subtypes. Of 2116 patients, 2055 (97%) achieved viral load undetectability of <50 copies/mL. Rates of viral load suppression by 12 months were 89%, 94%, and 97% with subtypes B, C, and A, respectively (figure 1). Suppression occurred more rapidly in patients with subtype C (univariate hazard ratio [HR], 1.31; 95% CI, 1.15–1.49) or subtype A (univariate HR, 1.48; 95% CI, 1.15–1.89) infection than in those with subtype B infection (table 2). The multivariate analysis showed only weak evidence of an overall subtype effect on time to undetectability (adjusted P=.08). However, the adjusted effects with subtype C (adjusted HR, 1.16; 95% CI, 1.01–1.33; P=.04) and subtype A (adjusted HR, 1.35; 95% CI, 1.04–1.74; P=.02) infection remained statistically significant. No evidence indicated that time to undetectability differed with other subtypes when compared with subtype B. For a typical patient, predicted median times to undetectability were 3.1, 2.8, and 2.6 months with subtypes B, C, and A, respectively. Time to undetectability was reanalyzed with undetectability defined as a viral load <400 copies/mL (rather than <50 copies/mL), with similar results (data not shown).

Figure 1
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Figure 1

Kaplan-Meier curves for virologic outcomes shown for the 3 most prevalent human immunodeficiency virus type 1 subtypes. A, Time to viral load undetectability. B, Time to virologic rebound.

Figure 2
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Figure 2

Mean CD4 cell count during follow-up time shown for the 3 most prevalent human immunodeficiency virus type 1 subtypes

Table 1
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Table 1

Characteristics of the study population at the date of starting HAART, stratified by HIV-1 subtype.

Table 2
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Table 2

Cox regression results for time to viral load undetectability (viral load, <50 copies/mL) after commencement of HAART.

Time to virologic rebound. Of the 2055 patients who achieved undetectable viral loads, 1906 (93%) did so within 12 months after starting HAART, and of these, 335 (18%) subsequently experienced virologic rebound. Virologic rebound events occurred more rapidly in patients with subtype C infection (univariate HR, 1.39; 95% CI, 1.02–1.89) than in those with subtype B infection (table 3), with 12% and 8%, respectively, experiencing virologic rebound by 12 months (figure 1). In the multivariate analysis (table 3), subtype showed no overall effect on virologic rebound (adjusted P=.36). However, weak evidence persisted to suggest that virologic rebound occurred more rapidly for patients with subtype C infection compared with subtype B infection (adjusted HR, 1.40; 95% CI, 1.00–1.95; P=.05). There was no evidence that time to virologic rebound differed with other subtypes when compared with subtype B. Predicted time until 10% of patients experienced virologic rebound was 19.7 months for a typical patient with subtype C infection, compared with 35.8 months for patients with subtype B infection.

Table 3
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Table 3

Cox regression results for time to virologic rebound (2 consecutive viral loads >1000 copies/mL or 1 viral load >1000 copies/mL followed by a treatment change).

Overall, 192 virologic rebounds (57%) were classified as being due to nonadherence (see Methods) or recognized treatment interruption. Analyzing the remaining 143 virologic rebounds in a multivariate model (table 3) showed no evidence of a different time to virologic rebound in any of the subtypes that were compared with subtype B (adjusted P=.95). Although we did not consider treatment changes in the analyses, there was no evidence for a difference in the rates of change between subtypes. Rates per 1 person-year of follow-up by subtype were 0.45 for subtype B, 0.40 for subtype C, 0.45 for subtype A, 0.37 for CRF_AG, 0.53 for subtype D, and 0.42 for other non-B subtypes (P=.14).

Effect of ethnicity and transmission group on virologic outcomes. Separate analyses of the effects of ethnicity and transmission group on virologic outcomes are given in tables 2 and 3. Time to undetectability was shorter in black African patients than in white patients (adjusted HR, 1.15; 95% CI, 1.01–1.30; P=.03) and for heterosexual women than for men who have sex with men (adjusted HR, 1.22; 95% CI, 1.07–1.41; P=.004). Thus, black Africans and heterosexual women experienced similar increased hazards of undetectability as patients infected with subtype C or subtype A infection. Ethnicity (adjusted P=.13) and transmission group (adjusted P=.48) showed no overall effect on time to virologic rebound. However, analysis of individual ethnic and transmission groups indicated that black Africans and heterosexual women had higher hazards of virologic rebound than did whites and men who have sex with men, respectively, showing effects in the same direction as those seen with subtype C infection.

Immunologic outcomes. Using the nearest CD4 cell count to each time point (within a 3-month window), the mean CD4 cell count for subtypes B, C, and A over time is shown in figure 2. Patients with subtype B infection showed higher baseline CD4 cell counts and maintained the advantage throughout follow-up compared with the other 2 subtypes. In a multivariate model adjusting for time-varying effects of subtype, baseline CD4 cell count, initial third drug in the regimen and calendar year of starting HAART, and main effects of initial backbone, baseline viral load, and age, there was no overall evidence for a difference in CD4 cell count among subtypes at 3 months (adjusted P=.31) or for a different rate of increase in CD4 cell count after 3 months (adjusted P=.49). There was some evidence that patients with subtype C infection had a lower CD4 cell count at 3 months compared with patients with subtype B infection (adjusted P=.04), but there was no evidence that the rate of increase in CD4 cell count after 3 months of therapy differed between subtypes B and C (adjusted P=.63). Predicted CD4 cell counts from the multivariate model are given in table 4. All predicted differences were small, with subtypes C, A, and D always predicted to have a CD4 cell count lower than subtype B.

Table 4
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Table 4

Immunologic responses in patients starting HAART.

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Discussion

As increasing numbers of patients infected with HIV-1 subtypes other than B access antiretroviral therapy worldwide, it is important to determine whether their virologic and immunologic responses are similar to those reported with subtype B infection, for which long-term outcome data have accumulated through the years. Good responses to HAART have been reported from developing countries where a variety of virus strains circulates, but comparisons of individual subtypes remain scarce [25–27]. Studies from western Europe and North America previously compared responses to HAART in patients with subtype B and non-B subtypes grouped together and suggested similar virologic outcomes during up to 24 months of therapy [15–20]. Non-B subtypes, however, are as divergent from each other as they are from subtype B, and grouping them together may mask important differences. Our cohort had sufficiently large numbers of patients with subtype C, subtype A, CRF_AG, or subtype D infection to allow separate comparisons with subtype B infection. We detected only a weak overall effect of subtype on time to undetectability and no overall effect on time to subsequent virologic rebound but demonstrated differences when subtype B infection was compared with subtype C and subtype A infection individually. Because of the relatively small numbers of other non-B subtypes, there may be other effects that the study did not have sufficient power to detect.

Patients with subtype C or subtype A infection achieved virologic suppression more rapidly than those with subtype B infection. The interpretation of this finding should take into account the lower baseline viral load in subtype C and subtype A relative to subtype B infection, although we adjusted for this possible confounder in the multivariate analysis. A lower viral load in some non-B subtype strains may reflect suboptimal performance of viral load assays developed using subtype B strain as the primary reference [28]. Virus- and host-related factors might also influence the replication rates of certain non-B subtype strains. The envelopes of subtype C and subtype A strains, for example, show significantly shorter V1-V2 loop sequences and fewer potential N-linked glycosylation sites than subtype B envelopes [29], a property that correlates with the viral load set point and possibly reflects greater susceptibility to neutralizing antibody. Reduced replicative efficiency of subtype C relative to subtype B has also been observed in vitro and related to a reduced avidity of CD4/CCR5 binding [30].

In previous studies, a high baseline viral load and use of suboptimal regimens prolonged the time to undetectability regardless of subtype [19], and ethnicity, rather than subtype, appeared to influence outcomes [16]. We observed a strong correlation among subtype, ethnicity, and transmission group, which prevented adjustment for these factors. This correlation is a reflection of the current parallel epidemics in the United Kingdom, where non-B subtype strains circulate predominantly among heterosexual black African men and women, whereas the subtype B strain predominates in white men who have sex with men [4, 5]. The non-B subtype infections are largely imported through immigration, although non-B subtype infections may also be transmitted within the country [31]. Unless significant numbers of white men who have sex with men become infected with non-B subtype viruses, however, the problem of ethnicity and transmission group acting as confounders cannot be resolved in Western cohorts. The dominance of infections with subtype C and subtype A in the United Kingdom reflects the predominantly South and East African origin of the immigrant populations. The strains are highly diverse, however, comprising most non-B subtypes and many CRFs and unclassified viruses.

Consistent with previous observations [32, 33], our cohort showed a remarkably low risk of virologic rebound after achieving undetectable viral loads. There was, however, a small increase in the risk of virologic rebound among patients with subtype C relative to those with subtype B. After excluding virologic rebounds possibly related to nonadherence (as indicated by viral load rebound to pretreatment levels) or occurring during a recognized treatment interruption, the difference was no longer apparent. Because most patients infected with subtype C strains were immigrants from sub-Saharan Africa, it can be proposed that cultural and socioeconomic factors play an important role in these patients' ability to maintain long-term adherence to treatment [34–36] and may also affect other determinants of treatment success, such as nutritional status and effective engagement with health care services. A role for socioeconomic determinants of adherence is suggested by the recent AIDS Clinical Trials Group A5095 trial, which detected a higher risk of virologic failure on efavirenz-containing regimens among black Americans relative to white Americans and found a significant correlation between race and adherence [37]. These findings indicate the need for targeted adherence support in these populations.

Small comparisons of subtype B versus non-B subtypes grouped together reported either similar [16, 38] or dissimilar [18] CD4 cell count gains during HAART, whereas a larger comparison found no significant differences after adjustment for possible confounders [20]. In our study, baseline CD4 cell counts were lower in patients infected with non-B subtype viruses than in those infected with subtype B virus. However, the rates of CD4 cell recovery were overall similar, indicating a comparable immunologic efficacy of HAART. Nonetheless, the CD4 cell count gap between subtype B, subtype C, and subtype A persisted during treatment. All UK residents and asylum seekers have equal and free access to medical care and antiretroviral treatment. Our findings underscore the importance of improving HIV diagnosis among immigrant populations because these patients often remain unaware of their infection until late in the disease course and are at significant risk of opportunist infections and mortality [39, 40].

In summary, our study, albeit limited by the observational nature of the cohort, is the first to report a large comparison of responses to starting HAART in patients infected with subtype B, subtype C, subtype A, CRF_AG, and subtype D. Virologic and immunologic responses were overall excellent during a median follow-up period of 39 months, indicating that current regimens are equally effective regardless of the infecting subtype. The observation of more rapid viral load suppression in subtype C and subtype A infection is of interest and warrants further investigation.

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Study Groups

UK Collaborative Group on HIV Drug Resistance

Steering committee. Jane Anderson, Homerton University Hospital, London; David Asboe and Anton Pozniak, Chelsea & Westminster Hospital, London; Sheila Burns, Royal Infirmary of Edinburgh; Sheila Cameron, Gartnavel General Hospital, Glasgow; Patricia Cane, Health Protection Agency, Porton Down; Ian Chrystie, Guy's and St. Thomas' NHS Foundation Trust, London; Duncan Churchill, Brighton and Sussex University Hospitals NHS Trust; Duncan Clark, St Bartholomew's and The London NHS Trust; Valerie Delpech and Deenan Pillay, Health Protection Agency, Centre for Infections, London; Linda Lazarus, Expert Advisory Group on AIDS Secretariat, Health Protection Agency, London; David Dunn, Esther Fearnhill, Hannah Green and Kholoud Porter, MRC Clinical Trials Unit, London; Philippa Easterbrook and Mark Zuckerman, King's College Hospital, London; Anna Maria Geretti, Royal Free NHS Trust, London; Paul Kellam, Deenan Pillay, Andrew Phillips and Caroline Sabin, Royal Free and University College Medical School, London; David Goldberg, Health Protection Scotland, Glasgow; Mark Gompels, Southmead Hospital, Bristol; Antony Hale, Leeds Teaching Hospitals NHS Trust; Steve Kaye, St. Mary's Hospital, London; Svilen Konov, Community Advisory Board; Andrew Leigh-Brown, University of Edinburgh; Nicola Mackie, St. Mary's Hospital, London; Chloe Orkin, St. Bartholomew's Hospital, London; Erasmus Smit, Health Protection Agency, Birmingham Heartlands Hospital; Peter Tilston, Manchester Royal Infirmary; Ian Williams, Mortimer Market Centre, London; and Hongyi Zhang, Addenbrooke's Hospital, Cambridge.

Participating laboratories. Addenbooke's Hospital, Cambridge (Hongyi Zhang); Department of Virology, St Bartholomew's and The London NHS Trust (Duncan Clark, Ines Ushiro-Lumb, Tony Oliver, David Bibby); Belfast Health and Social Care Trust (Suzanne Mitchell); HPA Birmingham Public Health Laboratory (Erasmus Smit); Chelsea and Westminster Hospital, London (Adrian Wildfire); Dulwich Hospital, London (Melvyn Smith); Royal Infirmary of Edinburgh (Jill Shepherd); West of Scotland Specialist Virology Lab Gartnavel, Glasgow (Alasdair MacLean); Guy's and St. Thomas' NHS Foundation Trust, London (Ian Chrystie); Leeds Teaching Hospitals NHS Trust (Diane Bennett); Specialist Virology Centre, Liverpool (Mark Hopkins) and Manchester (Peter Tilston); Department of Virology at Royal Free Hospital, London (Clare Booth, Ana Garcia-Diaz); St Mary's Hospital, London (Steve Kaye); and University College London Hospitals (Stuart Kirk).

The UK Collaborative HIV Cohort (UK CHIC) Study Group

Steering committee. Jonathan Ainsworth, Jane Anderson, Abdel Babiker, David Dunn, Philippa Easterbrook, Martin Fisher, Brian Gazzard (Chair), Richard Gilson, Mark Gompels, Teresa Hill, Margaret Johnson, Clifford Leen, Chloe Orkin, Andrew Phillips, Deenan Pillay, Kholoud Porter, Caroline Sabin, Tariq Sadiq, Achim Schwenk, Nicky Mackie, Alan Winston, and Valerie Delpech.

Central coordination. Medical Research Council Clinical Trials Unit (MRC CTU), London (David Dunn, Adam Glabay, Kholoud Porter); and Royal Free NHS Trust and RFUCMS, London (Loveleen Bansi, Teresa Hill, Andrew Phillips, Caroline Sabin).

Participating centers. Barts and The London NHS Trust, London (Chloe Orkin, Kevin Jones, Rachel Thomas); Brighton and Sussex University Hospitals NHS Trust (Martin Fisher, Nicky Perry, Anthony Pullin, Duncan Churchill); Chelsea and Westminster NHS Trust, London (Brian Gazzard, Steve Bulbeck, Sundhiya Mandalia, Jemima Clarke); Health Protection Agency—Centre for Infections London (HPA) (Valerie Delpech); Homerton University Hospital NHS Trust, London (Jane Anderson, Sajid Munshi); King's College Hospital, London (Philippa Easterbrook, Frank Post, Yasar Khan, Paragi Patel, Fatimah Karim, Stephen Duffell); Medical Research Council Clinical Trials Unit (MRC CTU), London (Abdel Babiker, David Dunn, Adam Glabay, Kholoud Porter); Mortimer Market Centre, Royal Free and University College Medical School (RFUCMS), London (Richard Gilson, Shuk-Li Man, Ian Williams); North Middlesex University Hospital NHS Trust, London (Achim Schwenk); Royal Free NHS Trust and RFUCMS, London (Margaret Johnson, Mike Youle, Fiona Lampe, Colette Smith, Helen Grabowska, Clinton Chaloner, Dewi Ismajani Puradiredja, Loveleen Bansi, Teresa Hill, Andrew Phillips, Caroline Sabin); St. Mary's Hospital, London (Nicky Mackie, Alan Winston, Jonathan Weber, Christian Kemble, Mark Carder); The Lothian University Hospitals NHS Trust, Edinburgh (Clifford Leen, Alan Wilson); and North Bristol NHS Trust (Mark Gompels, Debbie Dooley).

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Acknowledgments

Financial support. The UK HIV Drug Resistance Database is partly funded by the US Department of Health. Additional financial support is provided by Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Roche Pharmaceuticals, and Tibotec (a division of Janssen-Cilag Ltd).

Potential conflicts of interest. All authors: no conflicts.

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Footnotes

  • The views expressed in the publication are those of the authors and not necessarily those of the US Department of Health.

  • ↵A complete list of the members of the UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study is provided at the end of the text.

  • Received September 23, 2008.
  • Accepted January 6, 2009.
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  1. Clin Infect Dis. (2009) 48 (9): 1296-1305. doi: 10.1086/598502
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