Combination antiretroviral therapy (ART), in particular greater duration of protease inhibitor (PI) therapy, is associated with an increased risk of myocardial infarction [1–5]. This risk appears to be mediated in part by ART-associated dyslipidaemia and insulin resistance, as well as by traditional risk factors (increasing age, male sex, smoking and hypertension). In the Strategies for Management of Antiretroviral Therapy (SMART) study, intermittent ART was also associated with borderline increased short-term risk of cardiovascular events relative to continuous ART, the pathogenesis of which is unknown .
Asymptomatic electrocardiogram (ECG) findings specific for myocardial ischaemia (Q-waves and ST segment depression, and T-wave inversion in men) signify an increased risk of myocardial infarction or death in HIV-uninfected adults, regardless of whether patients develop symptomatic myocardial ischaemia [7–12]. No study has described the prevalence and type of asymptomatic, ischaemic ECG changes in HIV-infected adults and their association with demographics, clinical characteristics, traditional cardiovascular risk factors, HIV disease stage or use of ART.
The SMART study is an international, randomized trial comparing intermittent, CD4 lymphocyte count-guided ART versus continuous ART aimed at viral suppression in 5472 HIV-infected participants with CD4 cell counts > 350 cells/μl. Standardized, resting, 12-lead ECG records at baseline in SMART were evaluated to assess the prevalence of asymptomatic, resting, ischaemic ECG abnormalities and to determine the association of these ECG abnormalities with demographic and HIV disease characteristics, with traditional cardiovascular risk factors, and with the type and duration of ART.
Eligibility criteria for participation in SMART were documented HIV-1 infection, age greater than 13 years, CD4 cell count > 350 cells/μl and not pregnant or breast feeding. Written, informed consent was obtained from all participants at the 318 sites in 33 countries. Participants with prior, symptomatic ischaemic heart disease (IHD) were excluded from the present analysis.
Data collected at baseline were demography (age, sex, race/ethnicity, location, likely mode of HIV infection); history of symptomatic IHD (prior myocardial infarction, prior coronary artery disease requiring drug treatment or invasive procedure, prior congestive cardiac failure, or current use of antianginal drugs); cardiovascular risk profile [smoking status, hypertension (current antihypertensive therapy), history of diabetes mellitus, alcohol abuse (physician defined), and current lipid-lowering therapy]; clinical history; HIV disease status (known duration of HIV infection, prior clinical AIDS diagnosis, CD4 cell count and HIV viral load); duration of ART [any ART, PI therapy, nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) therapy]; body composition (patient report of peripheral lipoatrophy and/or increased abdominal girth, body mass index); and plasma lipids [total, direct low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, triglycerides], all measured centrally, with 1943 (48%) of 4013 baseline lipid samples collected from participants who had fasted for at least 12 h. Family history of IHD was not recorded.
Standard, 12-lead ECGs were recorded electronically using a GE Medical Systems Information Technologies MAC 1200 electrocardiograph (GEMSIT; Milwaukee, Wisconsin, USA) with participants in a supine or semirecumbent position and in a resting state. ECG measurements were performed by study-certified research staff. A simultaneous, 10 s recording sampled every 250 μs was transmitted electronically to a central reading facility (EPICARE, Wake Forest University, Winston-Salem, North Carolina, USA). The prevalence of each ECG abnormality was summarized using the Minnesota code , determined by automated (95.2%) or visual (4.8%) ECG readings.
Electrocardiography outcome measures
In the primary analysis, ischaemia was defined by presence of major or minor Q-waves (Minnesota codes 1.1, 1.2, 1.3) or ST segment depression (codes 4.1, 4.2, 4.3, 4.4) and was considered the primary endpoint. T-wave inversion (codes 5.1, 5.2, 5.3, 5.4) may signify ischaemia but is often a nonspecific finding in women. The composite outcome of Q-wave, ST segment depression and T-wave inversion was considered the secondary endpoint and was used in secondary analyses. These ECG abnormalities were chosen because they are strongly associated with symptomatic IHD and with an increased future risk of myocardial infarction and sudden death, regardless of cardiac symptoms [14–23]. The Minnesota coding system, therefore, has been very widely adopted.
Univariate and multivariate logistic regression was used to assess the association between asymptomatic ischaemia at baseline and patient characteristics; odds ratios (OR) for the prevalence of asymptomatic ischaemia were estimated with 95% confidence intervals (CI) and P values for tests of independence (no association) were calculated. In multivariate regression, four sets of variables were included sequentially: demographics (age, sex, race/ethnicity, likely mode of HIV infection, location of enrolment), clinical history (history of AIDS, hepatitis C antibody status, alcohol abuse, current smoking, antihypertensive therapy and body mass index), metabolic cardiovascular risk factors (history of diabetes mellitus, current lipid levels, current lipid-lowering therapy), and ART (duration of ART; PI and NNRTI use). Analysis of each set was adjusted for all variables within that set and any preceding set. Low levels of HDL cholesterol were defined as < 350 mg/l (0.9 mmol/l) in men and as < 450 mg/l (1.1 mmol/l) in women.
Only ART class associations were analysed, not individual drug associations, as the number of subjects taking each drug was relatively small, and it was considered likely that other parameters would not be matched between patients receiving drugs within a given drug class. Self-reported peripheral lipoatrophy was not included in the multivariate analysis as lipoatrophy is known to be influenced by ART type and duration; therefore, inclusion of lipoatrophy in the multivariate analyses would likely have confounded the ART associations under evaluation. Hepatitis C, but not hepatitis B, was analysed as a potential risk factor for ischaemic ECG abnormalities as hepatitis C is associated with insulin resistance.
To investigate the observed association of NNRTI use with the prevalence of asymptomatic IHD more closely, and also because of the lower incidence of IHD previously reported in those receiving NNRTI therapy compared with those receiving PI therapy , NNRTI use was further assessed in three separate multivariate regression analyses as (1) duration of NNRTI use in six categories; (2) ever used NNRTI versus NNRTI-naive; and (3) ever used NNRTI plus duration of use in years, adjusted for all the other factors.
The univariate association with IHD was assessed for each factor listed above, plus for current and nadir CD4 cell count, current HIV RNA, patient report of increased abdominal girth, lipoatrophy and use of ART and PI (ever versus never).
Analyses were performed for both the primary endpoint of Q-wave or ST depression, and the secondary endpoint that also included T-wave inversion. The regression analyses were also performed separately for men and women.
As a sensitivity analysis for assessing the effect of NNRTI use and PI use on the primary endpoint of asymptomatic IHD, the univariate OR values for IHD were assessed versus those who were ART naive for participants who had used NNRTI but no PI, and those who had used a PI but no NNRTI.
Statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina, USA). All tests were two-sided. P values should be interpreted with caution owing to the large number of factors investigated.
Of 5472 participants, 258 (4.7%) had no ECG prior to randomization and 187 (3.3%) had an unacceptable baseline ECG because of lead swapping (102), poor quality trace (78), atrial fibrillation (4) or Wolff–Parkinson–White syndrome (3). Of the 5027 participants with an evaluable baseline ECG, 196 (3.9%) reported a history of symptomatic IHD and were excluded.
Table 1 shows patient characteristics for the 4831 participants included in this analysis. Mean age was 44 years (SD, 9.3); 28.4% were female; 29.6% were black; 40.2% were smokers; 6.6% had diabetes; 16.5% were receiving antihypertensive therapy; and 14.2% were receiving lipid-lowering therapy. Overall, 95.4% of the included participants were ART experienced; 83.9% were taking ART at baseline. For ART-experienced participants, median ART duration was 6 years (interquartile range, 4–8). Of the 1372 women, 43.4% were black, as were 24.1% of the 3459 men.
Prevalence of electrocardiograph abnormalities
ECG evidence of asymptomatic IHD (Q-wave or ST segment depression) was detected in 526 participants (10.9%) with no known IHD: Q-waves in 283 (5.9%) and ST segment depression in 264 (5.5%) (Table 2). Q-waves or ST segment depression were observed in 388 (11.2%) men and 138 (10.1%) women. Prevalence by race (9.7% in blacks, 11.4% in nonblacks), location of enrolment (7.9% to 14.4%), cardiovascular risk factors and ART use is shown in Table 3 (column 2). T-wave inversion was observed in 534 participants (11.1%) and was substantially more common in women than in men (16.4% and 8.9%, respectively). The secondary endpoint of Q-waves, ST depression or T wave inversion was detected in 895 (18.5%) participants: 17.1% of men and 22.0% of women. Of the 196 participants with a history of prior IHD who were omitted from the primary analysis, Q-waves, ST depression and T-wave inversion were detected in 51 (26.0%), 43 (21.9%) and 71 (36.2%), respectively.
Risk factors for electrocardiograph abnormalities
Primary endpoint: Q-wave or ST depression
The three variables independently associated with the primary endpoint were older age (≥ 60 years compared with < 40 years: OR, 2.2; 95% CI, 1.5–3.2; P < 0.001), current antihypertensive therapy (OR, 1.5; 95% CI,1.1–1.9; P = 0.003) and location (participants in Europe compared with North America: OR, 1.4; 95% CI, 1.1–1.7; P = 0.004; participants in Asia compared with North America: OR, 1.6; 95% CI, 1.0–2.6; P = 0.05; Table 3). History of diabetes was also significant in the univariate but not multivariate analysis (P = 0.06). Presence of self-reported peripheral lipoatrophy was also significant in univariate analysis (OR, 1.3; 95% CI, 1.0–1.6; P = 0.03). No other traditional risk factors for IHD, including current smoking, abnormal lipid levels and current lipid-lowering therapy, or HIV disease characteristic were significantly associated with these abnormalities. Sensitivity analyses yielded similarly, nonsignificant results whether using lipids as two continuous variables or as the ratio of total cholesterol to HDL cholesterol as a single, linear variable (data not shown).
The prevalence of asymptomatic Q-wave or ST segment depression was 10.8% in those who had ever received ART and 12.1% in ART-naive participants (OR, 0.9; 95% CI, 0.6–1.4; P = 0.70). For men, the prevalence was 11.2% in those who had ever received ART compared with 10.7% in ART-naive men (OR, 1.1; 95% CI, 0.6–1.7; P = 0.82). For women, the prevalence rates were 9.9% and 14.8%, respectively (OR, 0.6; 95% CI, 0.3–1.4; P = 0.24). This apparent difference in prevalence by sex and ART experience was not statistically significant (P = 0.27 for interaction). Total ART duration was not associated with a higher prevalence of asymptomatic IHD.
In terms of ART, the prevalence of Q-wave or ST depression was 10.2% in those who had received an NNRTI and 12.1% for NNRTI-naive participants (OR, 0.8; 95% CI, 0.6–1.0; P = 0.05; Table 3, NNRTI analysis 2). However, duration of NNRTI exposure was not independently associated with prevalence of asymptomatic IHD (Table 3, NNRTI analysis 3). In contrast, the prevalence was 11.2% in those who had ever received a PI and 10.2% in PI-naive participants (univariate analysis: OR, 1.1; 95% CI, 0.9–1.4; P = 0.29); after adjustment, the OR for the prevalence of asymptomatic IHD in PI-experienced versus PI-naive participants was 0.9 (multiple regression: 95% CI, 0.7–1.1; P = 0.32). Sensitivity analyses in those who had never received a PI and in those who had never received an NNRTI found a similar, nonsignificant, reduced prevalence of asymptomatic IHD with NNRTI-based ART, and no association of prevalence with PI-based ART (data not shown).
In men, the following were significantly associated with the primary endpoint in multivariate analysis: older age; location in Europe, Asia and Africa compared with enrolment in the United States; and NNRTI use (ever versus. never in analysis 3: OR, 0.7; 95% CI, 0.5–1.0; P = 0.04), although there was no association with duration of NNRTI use in years. In analysis 1, only NNRTI duration of 1 to < 3 years compared with no NNRTI exposure was significant). In women, older age and current antihypertensive therapy were significantly associated (data not shown).
Secondary endpoint: Q-wave, ST segment depression, or T-wave inversion
For the secondary endpoint, older age and use of antihypertensive therapy were independently associated with asymptomatic IHD (data not shown). In contrast to the primary endpoint, men had significantly lower prevalence of the secondary endpoint than women, owing to the lower prevalence of T-wave inversions (Table 2). Prevalence was higher among blacks than nonblacks, in those with diabetes (OR, 1.4; 95% 1.0–1.8; P = 0.02) and in those with low HDL cholesterol levels (OR, 1.2; 95% 1.0–1.5; P = 0.03). Location of enrolment was not significant. Longer ART duration was independently associated with higher prevalence (5–7 years or > 7 years versus no use: P = 0.04 and P = 0.03, respectively). Similar to the primary endpoint, the association with NNRTI use was nonsignificant (in analysis 3 for ever versus NNRTI naive: OR, 0.8; 95% CI, 0.6–1.0; P = 0.09; OR/year of NNRTI use, 1.0; 95% CI, 0.9–1.1; P = 0.62).
ECG evidence of asymptomatic IHD was common (10.9% with Q-waves or ST depression) and substantially more prevalent than a history of symptomatic IHD (3.9%) in this large, diverse cohort of HIV-infected patients. Traditional factors significantly associated with asymptomatic ECG evidence of IHD were older age and current use of antihypertensive therapy (probably a surrogate for long-standing hypertension). Also, enrolment in Europe and possibly Asia were also associated with increased risk, univariately and after adjustment for demographic variables such as age, sex and race.
Of note, smoking and dyslipidaemia were not associated with major ECG evidence of asymptomatic IHD in this patient population. The reasons for this lack of association are unclear, although smoking has been found not to be associated with major or minor ischaemic ECG changes in several studies of healthy, presumably HIV-uninfected, adults [20–23]. Another possibility is that smoking status may have changed relatively recently prior to enrolment in the study in a large proportion of participants, as has been observed previously . Lifelong lipid levels may also have changed relatively recently in response to HIV infection or to initiation or withdrawal of specific ART regimens (84% of participants used ART at baseline, and 10% had previously taken ART but had interrupted ART prior to enrolment) and also may have changed from the effects of lipid-lowering therapy (used by 14%). The lack of association with lipid levels raises the possibility that a proportion of the increased evidence of IHD observed in HIV-infected participants may not be primarily a result of dyslipidaemia but be a result of other unmeasured factors.
We detected significant geographic variability in the prevalence of ischaemic ECG abnormalities, as has been observed in studies of otherwise healthy adults [15,16]. The reason for this finding is unclear and was not explained by differences in the prevalence of age, sex, race, smoking status, diabetes, antihypertensive therapy, lipid levels or type and duration of ART (data not shown). Indeed, the prevalence of antihypertensive therapy was greater in North America (22.8%) than in other regions (2.8% to 12.4%), as was the prevalence of diabetes (8.7% in North America and 2.2–7.2% in other regions).
The prevalence of Q-waves or ST depression in patients without prior IHD in SMART was 10.9%. In large cohorts of otherwise healthy adults in various countries or regions, the prevalence has ranged from 1 to 9% [14–19]. We did not formally compare prevalence in the general population with the SMART study population, as the available general population cohorts were not matched by age, race and sex, did not always define ischaemic ECG abnormalities identically and were not as geographically diverse. For example, of the 4831 participants in the present analysis, only about 1800 were enrolled in the United States, limiting the power of any comparison with the US National Health and Nutrition Examination Survey . Also, it is likely that the prevalence of traditional risk factors are not identical in these studies (for example, HIV-infected adults are typically leaner and more likely to be smokers than HIV-uninfected adults ).
How do our data compare with findings from other studies of cardiovascular disease in HIV-infected patients? The D:A:D study found that increasing age, hypertension and diabetes were significantly associated with myocardial infarction but, unlike our study, also reported significant associations with dyslipidaemia and smoking . The D:A:D study also found that a greater duration of ART, particularly a PI-containing regimen, was associated with a 16%/year greater relative risk of clinically diagnosed myocardial infarction, but found no similar increase in relative risk for those using an NNRTI without a PI. Bearing in mind the cross-sectional design of our analysis, the smaller sample and the different endpoint studied, we did not find that longer duration of total ART or PI exposure was significantly associated with an increasing prevalence of asymptomatic IHD. We found a trend, however, suggesting that participants who had ever received an NNRTI were less likely to have Q-waves or ST segment depressions than those who were NNRTI naive (OR, 0.8, P = 0.05), as well as a lower prevalence of the secondary endpoint including T-wave inversion (OR = 0.8, P = 0.007). Duration of NNRTI exposure, however, was not independently associated with prevalence of asymptomatic IHD. Long-term, concomitant nucleoside reverse transcriptase inhibitor therapy (e.g. stavudine and zidovudine), which induces dyslipidaemia and insulin resistance , may, with longer duration of use, gradually reduce any possible favourable effect of NNRTI therapy. The significant association of longer ART duration, but not with longer PI duration, with the expanded secondary ischaemic event that included T-wave inversion might reflect such an effect. Another possibility is that the known favourable effect of NNRTI therapy on increasing plasma HDL cholesterol levels may have been reversed over time because of waning virological suppression . It is also important to note that our study evaluated the prevalence of asymptomatic IHD rather than of symptomatic myocardial infarction. Lastly, it remains possible that the weak association with NNRTI therapy may be a chance result, given the multiple statistical comparisons performed.
The somewhat lower prevalence of ECG evidence of IHD noted in participants receiving NNRTI-containing regimens is also consistent with prospective data from the SMART study, in which intermittent ART may be associated with an increased risk of major cardiovascular events relative to continuous ART . This effect was more pronounced in those who interrupted baseline ART that did not include a PI, possibly owing to the adverse effect of NNRTI interruption on lipid parameters.
The univariate association of ECG changes of ischaemia with lipoatrophy, a recognized side effect of ART, raises the possibility that ART may be playing a role in the induction of these ECG abnormalities. Lipoatrophy, however, was subjectively assessed (and can be confused with wasting) and lipoatrophy has been associated with older age, so the association might be a chance finding or a reflection of older age.
One potential limitation of the study is the imperfect sensitivity and specificity of the ECG for IHD. As with all tests, the ECG is neither 100% sensitive nor specific, but it is the gold standard tool for assessing asymptomatic IHD in population studies [14–23] as ischaemic ECG abnormalities in a healthy population are associated with an increased risk of myocardial infarction or sudden death. To increase specificity, we excluded T-wave inversion from the primary endpoint, since T-wave inversions have lower specificity for IHD in women than in men. If the ECG abnormalities we included in the primary endpoint had poor specificity, then hypertension and increasing age would not have been associated with these abnormalities.
Our study has several additional limitations. It was cross-sectional and so the observed associations may not be causal. In particular, the associations observed with types of ART require prospective evaluation. Diagnoses of diabetes and hypertension were based on history of diabetes and use of antihypertensive drugs, respectively, rather than on glucose and blood pressure levels, which were not recorded. Therefore, these conditions may have been underestimated, in which case the true magnitude of risk associated with each condition cannot be precisely determined. We cannot state whether the overall prevalence of asymptomatic IHD differs significantly from the prevalence in the general HIV-uninfected population, as appropriate control data are currently not available. Our study also has several strengths: it is large, ethnically and geographically diverse, and ECG were recorded using a standardized method and were analysed centrally.
HIV-uninfected adults with asymptomatic myocardial ischaemia on a resting ECG have a significantly increased risk of myocardial infarction or of sudden death, with the relative risk varying according to study patients, sample size and duration of follow-up. The clinical significance of our data, however, remains to be determined. Prospective evaluation of participants in studies such as SMART are required to determine if the ischaemic ECG abnormalities detected are predictive of future clinical IHD or mortality in HIV-infected patients. Only then might the ECG become a routine assessment tool as part of the long-term care of adults with HIV infection. In the interim, the present data suggest that asymptomatic IHD occurs in about 10% of HIV-infected adults, particularly those who are older, diabetic and hypertensive. Such patients may merit closer follow-up or more aggressive cardiovascular protective interventions.
SMART was initiated by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and implemented in collaboration with regional coordinating centers in Copenhagen (Copenhagen HIV Programme), London (Medical Research Council, Clinical Trials Unit) and Sydney (National Centre in HIV Epidemiology and Clinical Research). Participating staff are listed below.
CPCRA Chair's Office and Operations Center: F. Gordin (group leader), E. Finley, D. Dietz, C. Chesson, M. Vjecha, B. Standridge, B. Schmetter, L. Grue, M. Willoughby, A. Demers.
Copenhagen Regional Coordinating Center: J.D. Lundgren, K.B. Jensen, A. Fau, L. Borup, M. Pearson, P.O. Jansson, B.G. Jensen, T.L. Benfield.
London Regional Coordinating Center: J.H. Darbyshire, A.G. Babiker, A.J. Palfreeman, S.L. Fleck.
Sydney Regional Coordinating Centre: D.A. Cooper, S. Emery, F.M. Drummond, S.A. Connor, C.S. Satchell, S. Gunn, S. Oka, M.A. Delfino, K. Merlin, C. McGinley.
Minneapolis Statistical and Data Management Center: J.D. Neaton, A. DuChene, M. Harrison, M. George, B. Grund, C. Hogan (deceased), E. Krum, G. Larson, C. Miller, R. Nelson, J. Neuhaus, M.P. Roediger, T. Schultz, L. Thackeray.
ECG Reading Center: Ronald Prineas, Charles Campbell.
Endpoint Review Committee: G. Perez (co-chair), A. Lifson (co-chair), D. Duprez, J. Hoy, C. Lahart, D. Perlman, R. Price, R. Prineas, F. Rhame, J. Sampson, J. Worley.
NIAID Data and Safety Monitoring Board: M. Rein (chair), R. DerSimonian (executive secretary), B.A. Brody, E.S. Daar, N.N. Dubler, T.R. Fleming, D.J. Freeman, J.P. Kahn, K.M. Kim, G. Medoff, J.F. Modlin, R. Moellering Jr, B.E. Murray, B. Pick, M.L. Robb, D.O. Scharfstein, J. Sugarman, A. Tsiatis, C. Tuazon, L. Zoloth.
NIH, NIAID: K. Klingman, S. Lehrman.
SMART clinical site investigators by country (SMART enrollment). Argentina (147): J. Lazovski, W.H. Belloso, J.A. Benetucci, S. Aquilia, V. Bittar, E.P. Bogdanowicz, P.E. Cahn, A.D. Casiró, I. Cassetti, J.M. Contarelli, J.A. Corral, A. Crinejo, L. Daciuk, D.O. David, G. Guaragna, M.T. Ishida, A. Krolewiecki, H.E. Laplume, M.B. Lasala, L. Lourtau, S.H. Lupo, A. Maranzana, F. Masciottra, M. Michaan, L. Ruggieri, E. Salazar, M. Sánchez, C. Somenzini; Australia (170): J.F. Hoy, G.D. Rogers, A.M. Allworth, JStC. Anderson, J. Armishaw, K; Barnes, A. Carr, A. Chiam, JC.P. Chuah, M.C. Curry, R.L. Dever, W.A. Donohue, N.C. Doong, D.E. Dwyer, J. Dyer, B. Eu, V.W. Ferguson, MA.H. French, R.J. Garsia, J. Gold, J.H. Hudson, S. Jeganathan, P. Konecny, J. Leung, C.L. McCormack, M. McMurchie, N. Medland, R.J. Moore, M.B. Moussa, D. Orth, M. Piper, T. Read, J.J. Roney, N. Roth, D.R. Shaw, J. Silvers, D.J. Smith, A.C. Street, R.J. Vale, N.A. Wendt, H. Wood, D.W. Youds, J. Zillman; Austria (16): A. Rieger, V. Tozeau, A. Aichelburg, N. Vetter; Belgium (95): N. Clumeck, S. Dewit, A. de Roo, K. Kabeya, P. Leonard, L. Lynen, M. Moutschen, E. O'Doherty; Brazil (292): L.C. Pereira Jr, TN.L. Souza, M. Schechter, R. Zajdenverg, MMT.B. Almeida, F. Araujo, F. Bahia, C. Brites, M.M. Caseiro, J. Casseb, A. Etzel, G.G. Falco, EC.J. Filho, S.R. Flint, C.R. Gonzales, JV.R. Madruga, L.N. Passos, T. Reuter, L.C. Sidi, AL.C. Toscano; Canada (102): D. Zarowny, E. Cherban, J. Cohen, B. Conway, C. Dufour, M. Ellis, A. Foster, D. Haase, H. Haldane, M. Houde, C. Kato, M. Klein, B. Lessard, A. Martel, C. Martel, N. McFarland, E. Paradis, A. Piche, R. Sandre, W. Schlech, S. Schmidt, F. Smaill, B. Thompson, S. Trottier, S. Vezina, S. Walmsley; Chile (49): M.J. Wolff Reyes, R. Northland; Denmark (19): L. Ostergaard, C. Pedersen, H. Nielsen, L. Hergens, I.R. Loftheim, K.B. Jensen; Estonia (5): M. Raukas, K. Zilmer; Finland (21): J. Justinen, M. Ristola; France (272): P.M. Girard, R. Landman, S. Abel, S. Abgrall, K. Amat, L. Auperin, R. Barruet, A. Benalycherif, N. Benammar, M. Bensalem, M. Bentata, J.M. Besnier, M. Blanc, O. Bouchaud, A. Cabié, P. Chavannet, J.M. Chennebault, S. Dargere, X. de la Tribonniere, T. Debord, N. Decaux, J. Delgado, M. Dupon, J. Durant, V. Frixon- Marin, C. Genet, L. Gérard, J. Gilquin, B. Hoen, V. Jeantils, H. Kouadio, P. Leclercq, J-D. Lelièvre, Y. Levy, C.P. Michon, P. Nau, J. Pacanowski, C. Piketty, I. Poizot-Martin, I. Raymond, D. Salmon, J.L. Schmit, M.A. Serini, A. Simon, S. Tassi, F. Touam, R. Verdon, P. Weinbreck, L. Weiss, Y. Yazdanpanah, P. Yeni; Germany (215): G. Fätkenheuer, S. Staszewski, F. Bergmann, S. Bitsch, J.R. Bogner, N. Brockmeyer, S. Esser, F.D. Goebel, M. Hartmann, H. Klinker, C. Lehmann, T. Lennemann, A. Plettenberg, A. Potthof, J. Rockstroh, B. Ross, A. Stoehr, J.C. Wasmuth, K. Wiedemeyer, R. Winzer; Greece (95): A. Hatzakis, G. Touloumi, A. Antoniadou, G.L. Daikos, A. Dimitrakaki, P. Gargalianos-Kakolyris, M. Giannaris, A. Karafoulidou, A. Katsambas, O. Katsarou, A.N. Kontos, T. Kordossis, M.K. Lazanas, P. Panagopoulos, G. Panos, V. Paparizos, V. Papastamopoulos, G. Petrikkos, H. Sambatakou, A. Skoutelis, N. Tsogas, G. Xylomenos; Ireland (2): C.J. Bergin, C.D. Care, D.H. Dockrell, B. Mooka; Israel (13): S. Pollack, M.G. Mamorksy, N. Agmon-Levin, R. Karplus, E. Kedem, S. Maayan, E. Shahar, Z. Sthoeger, D. Turner, I. Yust; Italy (88): G. Tambussi, V. Rusconi, C. Abeli, M. Bechi, A. Biglino, S. Bonora, L. Butini, G. Carosi, S. Casari, A. Corpolongo, M. De Gioanni, G. Di Perri, M. Di Pietro, G. D'Offizi, R. Esposito, F. Mazzotta, M. Montroni, G. Nardini, S. Nozza, T. Quirino, E. Raise; Japan (15): M. Honda, M. Ishisaka; Lithuania (4): S. Caplinskas, V. Uzdaviniene; Luxembourg (3): J.C. Schmit, T. Staub; Morocco (42): H. Himmich, K. Marhoum El Filali; New Zealand (7): G.D. Mills, T. Blackmore, J.A. Masters, J. Morgan, A. Pithie; Norway (17): J. Brunn, V. Ormasssen; Peru (57): A. La Rosa, O. Guerra, M. Espichan, L. Gutierrez, F. Mendo, R. Salazar; Poland (54): B. Knytz, A. Horban, E. Bakowska, M. Beniowski, J. Gasiorowski, J. Kwiatkowski; Portugal (73): F. Antunes, R.S. Castro, M. Doroana, A. Horta, K. Mansinho, A.C. Miranda, I.V. Pinto, E. Valadas, J. Vera; Russia (17): A. Rakhmanova, E. Vinogradova, A. Yakovlev, N. Zakharova; South Africa (26): R. Wood, C. Orrel; Spain (100): J. Gatell, J.A. Arnaiz, R. Carrillo, B. Clotet, D. Dalmau, A. González, Q. Jordano, A. Jou, H. Knobel, M. Larrousse, R. Mata, J.S. Moreno, E. Oretaga, J.N. Pena, F. Pulido, R. Rubio, J. Sanz, P. Viciana; Switzerland (91): B. Hirschel, R. Spycher, M. Battegay, E. Bernasconi, S. Bottone, M. Cavassini, A. Christen, C. Franc, H.J. Furrer, A. Gayet-Ageron, D. Genné, S. Hochstrasser, L. Magenta, C. Moens, N. Müller, R. Nüesch; Thailand (159): P. Phanuphak, K. Ruxrungtham, W. Pumpradit, P. Chetchotisakd, S. Dangthongdee, S. Kiertiburanakul, V. Klinbuayaem, P. Mootsikapun, S. Nonenoy, B. Piyavong, W. Prasithsirikul, P. Raksakulkarn; United Kingdom (214): B.G. Gazzard, W. Dodds, J.G. Ainsworth, J. Anderson, B.J. Angus, T.J. Barber, M.G. Brook, D.R. Chadwick, M. Chikohora, D.R. Churchill, D. Cornforth, P.J. Easterbrook, P.A. Fox, R. Fox, P.A. Gomez, M.M. Gompels, G.M. Harris, S. Herman, AG.A. Jackson, SP.R. Jebakumar, M.A. Johnson, G.R. Kinghorn, K.A. Kuldanek, N. Larbalestier, C. Leen, M. Lumsden, T. Maher, J. Mantell, R. Maw, S. McKernan, L. McLean, S. Morris, L. Muromba, C.M. Orkin, A.J. Palfreeman, B.S. Peters, TE.A. Peto, S.D. Portsmouth, S. Rajamanoharan, A. Ronan, A. Schwenk, M.A. Slinn, C.J. Stroud, R.C. Thomas, M.H. Wansbrough-Jones, H.J. Whiles, E. Williams, I.G. Williams, M. Youle; United States (2989): D.I. Abrams, E.A. Acosta, S. Adams, A. Adamski, L. Andrews, D. Antoniskis, D.R. Aragon, R. Arduino, R. Artz, J. Bailowitz, B.J. Barnett, C. Baroni, M. Barron, J.D. Baxter, D. Beers, M. Beilke, D. Bemenderfer, A. Bernard, C.L. Besch, M.T. Bessesen, J.T. Bethel, S. Blue, J.D. Blum, S. Boarden, R.K. Bolan, J.B. Borgman, I. Brar, B.K. Braxton, U.F. Bredeek, R. Brennan, D.E. Britt, J. Brockelman, S. Brown, V. Bruzzese, D. Bulgin-Coleman, D.E. Bullock, V. Cafaro, B. Campbell, S. Caras, J. Carroll, K.K. Casey, F. Chiang, G. Childress, R.B. Cindrich, C. Clark, M. Climo, C. Cohen, J. Coley, D.V. Condoluci, R. Contreras, J. Corser, J. Cozzolino, L.R. Crane, L. Daley, D. Dandridge, V. D'Antuono, J.G. Darcourt Rizo Patron, J.A. DeHovitz, E. DeJesus, J. DesJardin, M. Diaz-Linares, C. Dietrich, P. Dodson, E. Dolce, K. Elliott, D. Erickson, M. Estes, L.L. Faber, J. Falbo, M.J. Farrough, C.F. Farthing, P. Ferrell-Gonzalez, H. Flynn, C. Frank, M. Frank, K.F. Freeman, N. French, G. Friedland, N. Fujita, L. Gahagan, K. Genther, I. Gilson, M.B. Goetz, E. Goodwin, F. Graziano, C.K. Guity, P. Gulick, E.R. Gunderson, C.M. Hale, K. Hannah, H. Henderson, K. Hennessey, W.K. Henry, D.T. Higgins, S.L. Hodder, H.W. Horowitz, M. Howe-Pittman, J. Hubbard, R. Hudson, H. Hunter, C. Hutelmyer, M.T. Insignares, L. Jackson, L. Jenny, M. John, D.L. Johnson, G. Johnson, J. Johnson, L. Johnson, J. Kaatz, J. Kaczmarski, S. Kagan, C. Kantor, T. Kempner, K. Kieckhaus, N. Kimmel, B.M. Klaus, N. Klimas, J.R. Koeppe, J. Koirala, J. Kopka, J.R. Kostman, M.J. Kozal, A. Kumar, A. Labriola, H. Lampiris, C. Lamprecht, K.M. Lattanzi, J. Lee, J. Leggett, C. Long, A. Loquere, K. Loveless, C.J. Lucasti, R. Luskin-Hawk, M. MacVeigh, L.H. Makohon, S. Mannheimer, N.P. Markowitz, C. Marks, N. Martinez, C. Martorell, E. McFeaters, B. McGee, D.M. McIntyre, J. McKee, E. McManus, L.G. Melecio, D. Melton, S. Mercado, E. Merrifield, J.A. Mieras, M. Mogyoros, F.M. Moran, K. Murphy, D. Mushatt, S. Mutic, I. Nadeem, J.P. Nadler, R. Nahass, D. Nixon, S. O'Brien, A. Ognjan, M. O'Hearn, K. O'Keefe, P.C. Okhuysen, E. Oldfield, D. Olson, R. Orenstein, R. Ortiz, J. Osterberger, W. Owen, F. Parpart, V. Pastore-Lange, S. Paul, A. Pavlatos, D.D. Pearce, R. Pelz, G. Perez, S. Peterson, G. Pierone Jr, D. Pitrak, S.L. Powers, H.C. Pujet, J.W. Raaum, J. Ravishankar, J. Reeder, N. Regevik, N.A. Reilly, C. Reyelt, J. Riddell IV, D. Rimland, M.L. Robinson, A.E. Rodriguez, M.C. Rodriguez-Barradas, V. Rodriguez Derouen, R. Roland, C. Rosmarin, W.L. Rossen, J.R. Rouff, J.H. Sampson, M. Sands, C. Savini, S. Schrader, M.M. Schulte, C. Scott, R. Scott, H. Seedhom, M. Sension, A. Sheble-Hall, A. Sheridan, J. Shuter, L.N. Slater, R. Slotten, D. Slowinski, M. Smith, S. Snap, D.M. States, M. Stewart, G. Stringer, J. Sullivan, K.K. Summers, K. Swanson, I.B. Sweeton, S. Szabo, E.M. Tedaldi, E.E. Telzak, Z. Temesgen, D. Thomas, M.A. Thompson, S. Thompson, C. Ting Hong Bong, C. Tobin, J. Uy, A. Vaccaro, L.M. Vasco, I. Vecino, G.K. Verlinghieri, F. Visnegarwala, B.H. Wade, V. Watson, S.E. Weis, J.A. Weise, S. Weissman, A.M. Wilkin, L. Williams, J.H. Witter, L. Wojtusic, T.J. Wright, V. Yeh, B. Young, C. Zeana, J. Zeh; Uruguay (3): E. Savio, M. Vacarezza.
Sponsorship: This work is supported by NIAID, NIH grants U01AI042170 and U01AI46362.
Potential conflicts of interest: Andrew Carr has received research funding from Abbott and Roche; consultancy fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Roche; lecture sponsorships from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Merck; and has served on advisory boards for Bristol-Myers Squibb, GlaxoSmithKline and Roche.
Note: Clinical Trials.gov identifier: NCT00027352.
Note: Presented in part at the Thirteenth Conference on Retroviruses and Opportunistic Infections. Boston, February 2006 [abstract 736].