Methods

The Data Collection on Adverse Events of Anti-HIV Drugs (D: A:D) study is an international collaboration of 11 cohorts that follows 33,308 HIV type 1-infected patients at 212 clinics in Europe, the United States, and Australia. For the purpose of our analyses, an individual was defined as having hypertension if the individual had a systolic blood pressure of 1140 mm Hg, had a diastolic blood pressure of 190 mm Hg, or was receiving antihypertensive medication or angiotensin-converting enzyme inhibitors. Dyslipidemia was considered present if the individual had a total cholesterol level of ⩾6.2 mmol/L, had a highdensity lipoprotein (HDL) cholesterol level of ⩽0.9 mmol/L, had a triglyceride level of ⩾2.3 mmol/L, or was receiving lipidlowering drugs. Ten-year predicted risk of coronary heart disease was determined using the Framingham equation [15].

Outcomes. All incident cases of MI during follow-up were reported to the study coordinating office for validation and coding. Reported MIs were classified as definite, possible, or unclassifiable, according to criteria applied in theWorld Health Organization Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) study [16] and independently of knowledge of a patient's antiretroviral treatment history. Other validated outcomes included strokes (definitive or possible), invasive cardiovascular procedures (coronary artery angioplasty or bypass, or carotid endarterectomy), diabetes mellitus, and death.

Statistical analysis. Seven NRTIs (zidovudine, stavudine, didanosine, zalcitabine, lamivudine, abacavir, and tenofovir), 4 PIs (indinavir, nelfinavir, lopinavir-ritonavir, and saquinavir), and 2 NNRTIs (efavirenz and nevirapine) reached the prespecified follow-up requirements: an exposure time of at least 30,000 person-years of follow-up (PYFU) with a median individual postexposure follow-up of >1 year. In order to meet these thresholds, we combined the follow-up of patients exposed to indinavir with that of patients without concomitant ritonavir use; similarly, we combined the follow-up from patients exposed to saquinavir with that of patients without ritonavir. Thus, our main analyses describe associations between any exposure to these 2 drugs (saquinavir and indinavir) and the development of MI, regardless of concomitant ritonavir use. However, as a sensitivity analysis, we also explored the separate associations of each drug with MI risk when used with or without ritonavir; of note, these analyses were based on <30,000 PYFU and therefore should be interpreted with caution.

Determination of the risk of MI. Full details of the analytical approach have been described elsewhere [4, 17]. Individuals were followed up prospectively from enrolment in D: A:D to the date of the first occurrence of MI during prospective follow-up, the date of death, 6 months after a patient's last clinic visit, or 1 February 2008, which ever occurred first. As in previous analyses, each person's follow-up was divided into a series of consecutive 1-month periods, and a patient's cumulative and current exposure to each antiretroviral drug at the start of each period was determined (including exposure to treatment before enrollment in D:A:D). Each person's covariate data were also updated at the start of each month, permitting a time-varying analysis. Any follow-up and events that occurred in that patient-month were then attributed to the characteristics of the patient at the start of that month.

Relationships between exposure to each drug and MI. Poisson regression models (GENMOD procedure in SAS software, version 9.1; SAS) were used to quantify the relationship between exposure to each drug and the risk of MI. All P values quoted are 2-sided, and results for which P ! .05 were considered statistically significant. All regression models were also adjusted for patient demographic characteristics (age, sex, HIV transmission group, and ethnicity), calendar year, clinical cohort, cardiovascular risk factors that are unlikely to be associated with use of CART (smoking status, family history of CVD, previous cardiovascular event [including previous MIs], and body mass index), and exposure to each of the other antiretroviral drugs that was in use over the study period (the 13 drugs listed above, as well as ritonavir when used as a single PI, amprenavir, and atazanavir, which were all also used in smaller numbers of patients). Where numbers were sufficiently large, specific categories were generated for missing data to ensure that all individuals and observed events were included in the analyses. An approximate test of heterogeneity, based on the difference between the log-likelihoods from this main model (which included separate covariates representing exposure to each of the PIs) and a model that included only a covariate for exposure to PIs as a class, was performed to assess whether there was evidence that at least 1 PI drug had an association with MI that was different from the others.

The models described above did not adjust for factors that could lie on the causal pathway between receipt of each drug and the development of MI (eg, lipids and elevated blood pressure). Thus, we explored whether any effects could be mediated through changes in the levels of other risk factors for MI that may be modified by CART, including lipids (total cholesterol, HDL cholesterol, and triglyceride levels [log2-transformed]), systolic and diastolic blood pressure, glucose level, the presence of diabetes mellitus, physician-defined lipodystrophy, and the use of lipid-lowering therapy or antihypertensive medication. This was achieved by the incorporation of the latest measurements of these variables as time-updated covariates. All lipid measurements were included, regardless of fasting status. We also considered whether any effects could be explained by different responses of HIV RNA level or CD4⁺ cell count to CART in patients receiving the different drugs by incorporating the latest value for these variables as time-updated continuous covariates.

In our analyses, we assume that the risk of MI associated with exposure to each PI is persistent and does not diminish after discontinuation of that drug. Thus, when a patient discontinues a PI, any follow-up and events continue to be attributed to the level of exposure to the PI at the time of discontinuation. However, if patients at risk of CVD who are receiving drugs thought to be associated with an increased CVD risk are selectively switched away from these drugs, our approach may underestimate the associations of interest. We investigated this possibility by reclassifying any follow-up and events that occurred >6 months after discontinuation of each PI in such a way that they were no longer attributed to the previous drug.

Results

Characteristics of patients with MI. The 33,308 patients contributed a total of 178,835 PYFU to the analysis (median per person, 5.8 PYFU [interquartile range {IQR}, 3.9–7.5 PYFU]), over which time 580 patients experienced an MI (event rate, 3.2 events per 1000 PYFU [95% confidence interval {CI}, 3.0–3.5 events per 1000 PYFU]). Those experiencing an MI were mostly men (90.7%), white (59.5%), and infected with HIV through sex with men (57.4%) and had a median age at the time of MI of 49 years; cardiovascular risk profiles of the men experiencing an MI, as well as those of all other patients, are shown in Table 1. Of those who experienced an MI, 573 (98.8%) had been exposed to antiretroviral therapy, 114 of whom were not receiving therapy at the time of their MI. The median latest CD4⁺ cell count before the diagnosis of MI and the nadir CD4⁺ cell count were 440 cells/µL (IQR, 292–628 cells/µL) and 128 cells/µL (IQR, 50–240 cells/µL), respectively. For over half (302 [52.1%]) of the 580 patients who developed MI, the latest HIV RNA level was <50 copies/mL before the MI. Among all patients experiencing an MI, the 10-year predicted risk of coronary heart disease was known to be high (ie, >20%) in 18.1% and moderate (ie, 10%–20%) in 30.3%; in contrast, only 4.2% and 14.5% of those not experiencing an MI fell into the high- and moderate-risk categories, respectively.

The cardiovascular risk profiles of patients who had ever been exposed to any of the drugs are shown in Table 2 for each drug. Although some differences were apparent in the characteristics of patients exposed to each of the drugs, these differences were not large. Of note, the characteristics of patients exposed to abacavir and tenofovir were similar.

Risk of MI according to exposure to individual drugs. Incidence rates of MI according to cumulative exposure are shown in Figure 1 for the 4 PIs and 2 NNRTIs and in Figure 2 for the 7 NRTIs. Among the PIs, after adjustments (Table 3), there was a significantly increased risk of MI in patients with longer exposure to indinavir (relative rate [RR] per additional year, 1.12 [95% CI, 1.07–1.18]) or lopinavir-ritonavir (RR, 1.13 [95% CI, 1.05–1.21]), but there were no significant associations between MI risk and longer exposure to either nelfinavir (RR, 1.04 [95% CI, 0.98–1.11]) or saquinavir (RR, 1.04 [95% CI, 0.98-1.11]) (P=.03 for approximate test of heterogeneity between drugs from the PI class). In the sensitivity analyses, we also considered whether recent exposure to each PI was a stronger predictor of MI risk than was cumulative exposure—this was not the case. There were no significant associations between the development of MI and cumulative exposure to either efavirenz (RR, 1.02 [95% CI, 0.96–1.08]) or nevirapine (RR, 0.97 [95% CI, 0.92–1.03]). Of the NRTIs, the only significant association between MI risk and cumulative exposure was with abacavir (RR, 1.07 [95% CI, 1.00–1.14]); recent exposure to abacavir (RR, 1.70 [95% CI, 1.17–2.47]) or didanosine (RR, 1.41 [95% CI, 1.09–1.82]) were both associated with an increased risk of MI. There were no significant associations between MI risk and recent exposure to any of the other NRTIs; in particular, there was no association between the risk of MI and either cumulative (RR per year, 1.04 [95% CI, 0.91–1.18]) or recent (RR, 1.14 [95% CI, 0.85–1.53]) exposure to tenofovir.

Table 3 shows the associations between MI risk and recent use of abacavir and didanosine, as well as those between MI risk and cumulative exposure to abacavir, lopinavir-ritonavir, and indinavir after adjustment. Adjustment for these measurements had only minimal effect on the estimates. Further adjustment for latest CD4⁺ cell count and HIV RNA level also did not substantially modify any of the estimates.

Sensitivity analysis. The RR per year of exposure to indinavir when received with ritonavir (22,186 PYFU among individuals exposed to this combination) was 1.18 (95% CI, 1.07–1.30); that for individuals exposed to indinavir without concomitant exposure to ritonavir (57,961 PYFU) was 1.11 (95% CI, 1.05–1.18). Similarly, the RR per year of exposure to saquinavir was 1.06 (95% CI, 0.97–1.14; 24,727 PYFU) when received concomitantly with ritonavir, but it was 1.07 (95% CI, 0.97–1.20; 26,145 PYFU) when received without ritonavir.

When we reran the analyses in such a way that patient followup and events occurring >6 months after discontinuation of each PI no longer contributed to the risk associated with those drugs, the estimates from the model were modified only slightly (eg, the RR associated with each year of exposure to lopinavirritonavir decreased from 1.13 to 1.12, whereas that for exposure to indinavir increased from 1.12 to 1.14).

Discussion

We examined the association between exposure to 13 antiretroviral drugs from the 3 main drug classes and the risk of MI. Of the drugs examined, cumulative exposure to indinavir (with or without ritonavir boosting), lopinavir-ritonavir, and abacavir, as well as recent exposure to abacavir and, to a lesser extent, didanosine, were each associated with an increased risk of MI. No increased risk of MI was noted with use of other NRTIs, including tenofovir, or with use of efavirenz or nevirapine. As in previous analyses, the associations between MI risk and either lopinavir-ritonavir or indinavir did not appear to be fully explained by an increased risk of dyslipidemia in patients with longer exposure to these drugs.

Of interest, the associations reported for the 2 PIs (12% per year for indinavir and 13% per year for lopinavir-ritonavir) are both slightly lower than that previously reported from the D: A:D study for the PI drug class as a whole (16% per additional year) [5]. Our previously reported findings were not, however, adjusted for exposure to NRTIs, either as a class or as individual drugs. There are differences between the individual drugs from the PI class in their propensity to cause metabolic disturbances [8–15]. In particular, lopinavir-ritonavir can cause elevated triglyceride levels [9, 18, 19], whereas indinavir (particularly when used with concomitant ritonavir) and saquinavir are both associated with the development of other lipid perturbations [20, 21]. Two recent trials showed that ritonavir-boosted saquinavir was associated with a better lipid profile than was lopinavirritonavir [22, 23], although the significant difference between the 2 drugs in the ratio between fasting total cholesterol level and HDL level was not detected at 48 weeks after randomization [23]. The associations that we found between MI risk and exposure to saquinavir were similarly not affected by concomitant exposure to ritonavir. Furthermore, although the reported associations between MI risk and exposure to indinavir and lopinavir-ritonavir were reduced slightly after adjustment for changes in lipids, these reductions were small (from 1.12 to 1.08 for indinavir and from 1.13 to 1.09 for lopinavir-ritonavir). Taken together, our results would suggest that the increased risk of MI found in patients receiving these PIs may not solely be a consequence of the dyslipidemia caused by these drugs.

Other possible explanations for the increased risk of MI associated with exposure to some of the PIs may include increased inflammation and coagulation. A recent article reported that the PI drug class was associated with increased levels of fibrinogen [24]. Of interest, in that study the levels of fibrinogen were higher in patients receiving PIs (particularly lopinavirritonavir) compared with those receiving NNRTIs.

Although the risk associated with each additional year of exposure to indinavir and lopinavir-ritonavir appears to be modest, the extent of exposure to each drug must be taken into account when assessing individual risk. Our preliminary analyses (Figure 1) demonstrated that the risk of MI increases with longer exposure to each drug, unlike the MI risk associated with NRTIs; because patients are seldom treated with PIs for only a single year, our estimates will translate into a clinically relevant risk when considered over a longer period of time. For example, our estimates would suggest that 5 years of exposure to lopinavir-ritonavir would be associated with an increased risk of MI of 84%, an excess risk that is roughly equivalent to that associated with aging by 10 years (which is associated with an 80% increased risk of MI in the same analysis).

Newer drugs within the PI class, in particular atazanavir, have been reported to cause fewer lipid perturbations [25, 26] than does lopinavir-ritonavir and has been reported to cause dyslipidemia to an extent similar to that caused by ritonavirboosted saquinavir [26, 27]. Additional follow-up will allow us to explore the risk of MI associated with atazanavir use, as well as with use of more recently introduced PIs, such as darunavir.

Individual drugs from the NRTIs. As previously reported, we found that recent exposure to abacavir and, to a lesser extent, didanosine were associated with an increased risk of MI. The increased risk associated with recent exposure to abacavir was, however, diminished [6], while at the same time, a slight in creased risk associated with cumulative exposure to abacavir was found. These changes may simply reflect chance findings, because exposure to this drug has increased (both estimates remain within the CIs previously reported). However, it may be that increased exposure to the drug has allowed us to more accurately capture the risk associated with cumulative exposure to the drug, which was previously undetectable, or that rapid changes in patient management have meant that some of those at highest risk of an MI have already switched away from abacavir to other drugs. Since the publication of our earlier findings on this drug, several studies have presented data to support an association between abacavir use and MI risk [28–30], whereas others have presented data that does not support this association [31, 32]. An explanation for the different findings of these studies remains to be elucidated, although study design (observational vs experimental), patient inclusion criteria, concomitant use of PIs, and duration of follow-up may all play a role.

There have been reports of associations between tenofovir and several renal toxicities [33–35]. However, the drug is thought to cause fewer lipid perturbations than do other NRTIs [36, 37]. In the present analysis, neither cumulative nor recent exposure to the drug was associated with an excess risk of MI, although CIs remain wide, reflecting the relatively recent introduction of this drug into routine use and hence the limited total exposure time. There have been concerns that our findings regarding abacavir exposure may simply reflect channeling bias, whereby individuals at the highest risk of MI (as determined through traditional CVD risk factors) may have been preferentially treated with this drug. Although we have previously provided arguments against this hypothesis [6], our experience suggests that tenofovir has also tended to be used preferentially in individuals with known higher CVD risk (and our present analysis would suggest that the cardiovascular risk factors of those exposed to tenofovir are not markedly different from the risk factors of those exposed to abacavir). Thus, if for some reason our analyses are unable to remove any bias that results from channeling, then we would expect to see an (artifactual) association between MI risk and tenofovir exposure similar to the association found with abacavir exposure. Of note, recent suggestions that the association between MI risk and abacavir may be a consequence of channeling patients at risk of chronic kidney disease (a risk factor for CVD) away from antiretroviral drugs with known adverse effects (particularly tenofovir and indinavir) do not appear to be supported in our study [38].

Individual drugs from the NNRTIs. We did not observe any associations between the development of MI and recent or cumulative exposure to either nevirapine or efavirenz, consistent with previous findings on this drug class [5]. Although efavirenz has been reported to cause elevated triglyceride levels [13, 14, 39], these increases do not appear to translate into an increased risk of clinical CVD. Recent studies have reported that nevirapine is associated with increases in HDL [40, 41], suggesting that the drug may have beneficial effects on cardiovascular risk. Of note, whereas the relative risk associated with cumulative exposure to nevirapine was<1, suggesting a possible cardioprotective role, this association was not strong and was not statistically significant (P=.34).

Limitations. We did not formally adjust P values to take account of the multiple tests performed. This is in line with many other analyses of cohort studies in which the value of such adjustments is debated [42, 43]. We have focused our attention only on associations that are robust in sensitivity analyses and highly significant, which suggests that they are unlikely to be chance findings. As with any observational study, our findings cannot be assumed to reflect causal associations and must be interpreted cautiously because of the potential for unmeasured confounding. Although an optimal study design would require the use of a randomized trial, the large sample size and follow-up required for such a trial renders it unlikely to be feasible. HIV treatment patterns are complex [44], and any analysis of treatment exposure in an observational study will always reflect a simplification of a more complex reality. Finally, our findings suggest that, within the PI drug class, some PIs (ie, indinavir and lopinavir-ritonavir) are associated with a stronger MI risk than are others. Although an approximate test of heterogeneity suggested some evidence that the different drugs within the PI class do have different propensity to cause MI, the P value from this test was only marginally significant (P=.02), and the CIs for the individual estimates do overlap. Thus, additional follow-up will allow us to more fully explore possible differences between drugs within the PI class.

In summary, we examined the risk of MI associated with exposure to individual antiretroviral drugs from 3 major drug classes in this large prospective cohort study. Of the individual drugs examined, indinavir, lopinavir-ritonavir, abacavir, and didanosine were all associated with an increased risk of MI. This risk appeared to increase with cumulative exposure to the 2 PIs and could partly be explained by the dyslipidemia caused by these drugs. In contrast, associations between MI risk and abacavir and didanosine exposure were largely confined to those patients with recent exposure to the drugs and did not appear to be driven by dyslipidemia. The overall rate of MI remains relatively low in this study, and any toxicities of antiretroviral drugs must always be interpreted in the context of the benefits that these drugs provide, but our findings do highlight the need for studies to continue to examine the complications associated with specific antiretroviral drugs.

Financial Support

Oversight Committee for the Evaluation of Metabolic Complications of Highly Active Antiretroviral Therapy (HAART; collaborative committee with representation from academic institutions, the European Agency for the Valuation of Medicinal Products, the US Food and Drug Administration, the patient community, and all pharmaceutical companies with licensed anti-HIV drugs in the US market: Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, and Hoffman-La Roche); Health Insurance Fund Council, Amstelveen, the Netherlands (grant CURE/97-46486 to the AIDS Therapy Evaluation Project Netherlands); Agence Nationale de Recherches sur le SIDA (Action Coordonnée no. 7, Cohortes; grant to the Aquitaine Cohort); Australian Government Department of Health and Ageing (funds to Australian HIV Observational Database [AHOD]); National Institute of Allergy and Infectious Diseases, US National Institutes of Health (grant U01-AI069907 to AHOD, grants 5U01AI042170- 10 and 5U01AI046362-03 to the Terry Beirn Community Programs for Clinical Research on AIDS); Foundation for AIDS Research (grant to AHOD); Fondo de Investigaciín Sanitaria (grant FIS 99/0887 to the Barcelona Antiretroviral Surveillance Study [BASS]); Fundaciín para la Investigaciín y la Prevenciín del SIDA en Espanã (grant FIPSE 3171/00 to BASS); BIOMED 1 (grant CT94-1637 to the EuroSIDA study); BIOMED 2 (grant CT97-2713 to the EuroSIDA study); Fifth Framework Program of the European Commission (grant QLK2-2000-00773 to the EuroSIDA study); Bristol-Myers Squibb (grant to the EuroSIDA study and unrestricted educational grant to the Italian Cohort Naive to Antiretrovirals [ICONA] Foundation]); GlaxoSmith- Kline (grant to the EuroSIDA study and unrestricted educational grant to the ICONA Foundation); Boehringer Ingelheim (grant to the EuroSIDA study and unrestricted educational grant to the ICONA Foundation); Hoffman-La Roche (grant to the EuroSIDA study); Abbott (unrestricted educational grant to the ICONA Foundation); Gilead (unrestricted educational grant to the ICONA Foundation); Pfizer (unrestricted educational grant to the ICONA Foundation); Janssen-Cilag (unrestricted educational grant to the ICONA Foundation); Swiss National Science Foundation (grant to the Swiss HIV Cohort Study).

Data Collection on Adverse Events of ANTI-HIV Drugs (D:A:D) Study Group Members

D:A:D central coordination. S. W. Worm, N. Friis-Moller, C. A. Sabin, A. Sjøl (verification of primary endpoint), and J. D. Lundgren.

D:A:D data managers. A. Sawitz (coordinator), M. Rickenbach, P. Pezzotti, E. Krum, L. Gras, E. Balestre, A. Sundström, M. Delforge, E. Fontas, F. Torres, K. Petoumenos, and J. Kjær.

D:A:D steering committee. S. Collins, S. Storpher, D. Pizzutti, and I. Weller.

AIDS Therapy Evaluation Project Netherlands (ATHENA; the Netherlands). Central coordination: F. deWolf, S. Zaheri, and L. Gras. Participating physicians: W. Bronsveld and M. E. Hillebrand-Haverkort (Alkmaar); J. M. Prins, J. C. Bos, J. K. M. Eeftinck Schattenkerk, S. E. Geerlings, M. H. Godfried, J. M. A. Lange, F. C. van Leth, S. H. Lowe, J. T. M. van der Meer, F. J. B. Nellen, K. Pogány, T. van der Poll, P. Reiss, T. A. Ruys, R. Sankatsing, R. Steingrover, G. van Twillert, M. van der Valk, M. G. A. van Vonderen, S. M. E. Vrouenraets, M. van Vugt, F. W. M. N. Wit, A. van Eeden, J. H. ten Veen, P. S. van Dam, J. C. Roos, K. Brinkman, P. H. J. Frissen, H. M. Weigel, J. W. Mulder, E. C. M. van Gorp, P. L. Meenhorst, A. T. A. Mairuhu, J. Veenstra, S. A. Danner, M. A. Van Agtmael, F. A. P. Claessen, R. M. Perenboom, A. Rijkeboer, and M. van Vonderen (Amsterdam); C. Richter, J. van der Berg, and R. van Leusen (Arnhem); R. Vriesendorp, F. J. F. Jeurissen, R. H. Kauffmann, E. L. W. Koger, and HAGA (Den Haag); B. Bravenboer (Eindhoven); C. H. H. ten Napel and G. J. Kootstra (Enschede); H. G. Sprenger, W. M. A. J. Miesen, R. Doedens, and E. H. Scholvinck (Groningen); R. W. ten Kate (Haarlem); D. P. F. van Houte and M. Polee (Leeuwarden); F. P. Kroon, E. F. van den Broek, J. T. van Dissel, and E. F. Schippers (Leiden); G. Schreij, S. van de Geest, and A. Verbon (Maastricht); P. P. Koopmans, M. Keuter, F. Post, and A. J. A. M. van der Ven (Nijmegen); M. E. van der Ende, I. C. Gyssens, M. van der Feltz, J. G. den Hollander, S. de Marie, J. L. Nouwen, B. J. A. Rijnders, and T. E. M. S. de Vries (Rotterdam); J. R. Juttmann, C. van de Heul, and M. E. E. van Kasteren (Tilburg); M. M. E. Schneider, M. J. M. Bonten, J. C. C. Borleffs, P. M. Ellerbroek, I. M. Hoepelman, C. A. J. J. Jaspers, I. Schouten, and C. A. M. Schurink (Utrecht); W. L. Blok and A. A. Tanis (Vlissingen); and P. H. P. Groeneveld (Zwolle).

Aquitaine (France). Scientific committee: R. Salamon (chair), J. Beylot, M. Dupon, M. Le Bras, J. L. Pellegrin, and J. M. Ragnaud. Central coordination: F. Dabis, G. Chêne, H. Jacqmin-Gadda, R. Thiébaut, S. Lawson-Ayayi, V. Lavignolle, E. Balestre, M. J. Blaizeau, M. Decoin, A. M. Formaggio, S. Delveaux, S. Labarerre, B. Uwamaliya, E. Vimard, L. Merchadou, G. Palmer, D. Touchard, D. Dutoit, F. Pereira, and B. Boulant. Participating physicians: J. Beylot, P. Morlat, N. Bernard, M. Bonarek, F. Bonnet, B. Coadou, P. Gelie, D. Jaubert, C. Nouts, D. Lacoste, M. Dupon, H. Dutronc, G. Cipriano, S. Lafarie, I. Chossat, J. Y. Lacut, B. Leng, J. L. Pellegrin, P. Mercié, J. F. Viallard, I. Faure, P. Rispal, C. Cipriano, S. Tchamgoué, M. Le Bras, F. Djossou, D. Malvy, J. P. Pivetaud, J. M. Ragnaud, D. Chambon, C. De La Taille, T. Galperine, S. Lafarie, D. Neau, A. Ochoa, C. Beylot, M. S. Doutre, J. H. Bezian, J. F. Moreau, J. L. Taupin, C. Conri, J. Constans, P. Couzigou, L. Castera, H. Fleury, M. E. Lafon, B. Masquelier, I. Pellegrin, P. Trimoulet, F. Moreau, C. Mestre, C. Series, and A. Taytard (Bordeaux).

Australian HIV Observational Database (AHOD; Australia). Central coordination: M. Law and K. Petoumenos (Sydney, New South Wales). Participating physicians: J. Anderson, P. Cortossis, J. Hoy, K. Watson, N. Roth, and J. Nicholson (Melbourne, Victoria); M. Bloch, T. Franic, D. Baker, R. McFarlane, A. Carr, and D. Cooper (Sydney, New SouthWales); J. Chuah and W. Fankhauser (Gold Coast, Queensland); and S. Mallal and C. Forsdyke (Perth, Western Australia).

Barcelona Antiretroviral Surveillance Study (BASS; Spain). Central coordination: G. Calvo, F. Torres, and S. Mateu (Barcelona). Participating physicians: P. Domingo, M. A. Sambeat, J. Gatell, E. Del Cacho, J. Cadafalch, and M. Fuster (Barcelona); and C. Codina, G. Sirera, and A. Vaqué (Badalona).

Brussels St Pierre Cohort (Belgium). N. Clumeck, S. De Wit, M. Gerard, K. Kabeya, D. Konopnicki, A. Libois, M. C. Payen, M. Delforge, and Y. Van Laethem.

Community Programs for Clinical Research on AIDS (CPCRA; United States). Central coordination: J. Neaton, G. Bartsch, W. M. El-Sadr, E. Krum, G. Thompson, and D. Wentworth. Participating physicians: R. Luskin-Hawk (Chicago, Illinois); E. Telzak (Bronx, New York); W. M. El-Sadr (Harlem, New York); D. I. Abrams (San Francisco, California); D. Cohn (Denver, Colorado); N. Markowitz and L. R. Crane (Detroit, Michigan); R. Arduino (Houston, Texas); D. Mushatt (New Orleans, Louisiana); G. Friedland (New Haven, Connecticut); G. Perez (Newark, New Jersey); E. Tedaldi (Philadelphia, Pennsylvania); E. Fisher (Richmond, Virginia); F. Gordin (Washington, DC); J. Sampson (Portland, Oregon); and J. Baxter (Camden, New Jersey).

EuroSIDA (multinational). Central coordination: O. Kirk, A. Mocroft, M. Ellefson, A. N. Phillips, and J. D. Lundgren. Participating countries and physicians: Argentina: M. Losso (national coordinator) and C. Elias. Austria: N. Vetter (national coordinator) and R. Zangerle (national coordinator). Belarus: I. Karpov (national coordinator), A. Vassilenko, V. M. Mitsura, and O. Suetnov. Belgium: N. Clumeck (national coordinator), L. Vandekerckhove (national coordinator), S. De Wit, B. Poll, and R. Colebunders. Bosnia: V. Hadziosmanovic (national coordinator). Bulgaria: K. Kostov (national coordinator). Croatia: I. Begovac (national coordinator). Czech Republic: L. Machala (national coordinator), H. Rozsypal, and D. Sedlacek. Denmark: J. Nielsen (national coordinator), G. Kronborg, T. Benfield, M. Larsen, J. Gerstoft, T. Katzenstein, A.-B. E. Hansen, P. Skinhoj, C. Pedersen, and L. Oestergaard. Estonia: K. Zilmer (national coordinator) and J. Smidt. Finland: M. Ristola (national coordinator). France: C. Katlama (national coordinator), J.-P. Viard, P.-M. Girard, J. M. Livrozet, P. Vanhems, C. Pradier, F. Dabis, and D. Neau. Germany: J. Rockstroh (national coordinator), R. Schmidt, J. van Lunzen, O. Degen, H. J. Stellbrink, S. Staszewski, J. Bogner, and G. Fa"tkenheuer. Greece: J. Kosmidis (national coordinator), P. Gargalianos, G. Xylomenos, J. Perdios, G. Panos, A. Filandras, E. Karabatsaki, and H. Sambatakou. Hungary: D. Banhegyi (national coordinator). Ireland: F. Mulcahy (national coordinator). Israel: I. Yust (national coordinator), D. Turner, M. Burke, S. Pollack, G. Hassoun, and S. Maayan. Italy: A. Chiesi (national coordinator), R. Esposito, I. Mazeu, C. Mussini, C. Arici, O. Riuniti, R. Bergamo, F. Pristera, F. Mazzotta, A. Gabbuti, V. Vullo, M. Lichtner, A. Chirianni, E. Montesarchio, M. Gargiulo, G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, A. Lazzarin, R. Finazzi, M. Galli, A. Ridolfo, and A. d'Arminio Monforte. Latvia: B. Rozentale (national coordinator) and P. Aldins. Lithuania: S. Chaplinskas (national coordinator). Luxembourg: R. Hemmer (national coordinator) and T. Staub. Netherlands: P. Reiss (national coordinator). Norway: J. Bruun (national coordinator), A. Maeland, and V. Ormaasen. Poland: B. Knysz (national coordinator), E. Jablonowska (national coordinator), J. Gasiorowski, A. Horban, E. Bakowska, D. Prokopowicz, R. Flisiak, A. Boron-Kaczmarska, M. Pynka, M. Beniowski, E. Mularska, H. Trocha, E. Malolepsza, and K. Wojcik. Portugal: F. Antunes (national coordinator), E. Valadas, K. Mansinho, and F. Maltez. Romania: D. Duiculescu (national coordinator). Russia: A. Rakhmanova (national coordinator), E. Vinogradova, and S. Buzunova. Serbia: D. Jevtovic (national coordinator). Slovakia: M. Mokráŝ (national coordinator) and D. Staneková. Slovenia: J. Tomazic (national coordinator). Spain: J. González-Lahoz (national coordinator), S. Moreno (national coordinator), V. Soriano, L. Martin-Carbonero, P. Labarga, B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, J. M. Gatell, J. M. Miró , P. Domingo, M. Gutierrez, G. Mateo, and M. A. Sambeat. Sweden: A. Karlsson (national coordinator), P. O. Persson, and L. Flamholc. Switzerland: B. Ledergerber (national coordinator), R. Weber, P. Francioli, M. Cavassini, B. Hirschel, E. Boffi, H. Furrer, M. Battegay, and L. Elzi. Ukraine: E. Kravchenko (national coordinator), G. Kutsyna (national coordinator), S. Servitskiy (national coordinator), S. Antoniak (national coordinator), M. Krasnov (national coordinator) and N. Chentsova. United Kingdom: S. Barton (national coordinator), A. M. Johnson, D. Mercey, A. Phillips, M. A. Johnson, A. Mocroft, M. Murphy, J. Weber, G. Scullard, M. Fisher, and C. Leen.

HivBivus (Sweden). Central coordination: L. Morfeldt, G. Thulin, and A. Sundström. Participating physicians: B. Å kerlund (Huddinge); K. Koppel and A. Karlsson (Stockholm); and L. Flamholc and C. Håkangård (Malmö).

Italian Cohort Naive to Antiretrovirals (ICONA) Foundation (Italy). Governing body: M. Moroni (Chair), G. Carosi, R. Cauda, F. Chiodo, A. d'Arminio Monforte, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, F. Mazzotta, R. Panebianco, G. Pastore, and C.F. Perno. Scientific secretary: A. d'Arminio Monforte. Steering committee: A. Ammassari, A. Antinori, C. Balotta, P. Bonfanti, M. R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, A. Cozzi-Lepri, A. d'Arminio Monforte, A. De Luca, C. Gervasoni, E. Girardi, S. Lo Caputo, F. Maggiolo, R. Murri, C. Mussini, M. Puoti, and C. Torti. Statistical and monitoring team: A. Cozzi-Lepri, I. Fanti, T. Formenti, and M. Prosperi. Participating physicians: M. Montroni, A. Giacometti, A. Costantini, and A. Riva (Ancona); U. Tirelli and F. Martellotta (Aviano-PN); G. Pastore and N. Ladisa (Bari); F. Suter and F. Maggiolo (Bergamo); F. Chiodo, G. Verucchi, and C. Fiorini (Bologna); G. Carosi, G. Cristini, C. Torti, C. Minardi, and D. Bertelli (Brescia); T. Quirino and C. Abeli (Busto Arsizio); P. E. Manconi and P. Piano (Cagliari); J. Vecchiet and M. Farenga (Chieti); G. Carnevale and S. Lorenzotti (Cremona); F. Ghinelli and L. Sighinolfi (Ferrara); F. Leoncini, F. Mazzotta, M. Pozzi, and S. Lo Caputo (Firenze); G. Pagano, G. Cassola, G. Viscoli, A. Alessandrini, and R. Piscopo (Genova); F. Soscia and L. Tacconi (Latina); A. Orani and R. Rossotto (Lecco); D. Tommasi and P. Congedo (Lecce); A. Chiodera and P. Castelli (Macerata); M. Galli, A. Lazzarin, G. Rizzardini, I. Schlacht, A. d'Arminio Monforte, A. L. Ridolfo, A. Foschi, A. Castagna, S. Salpietro, S. Merli, S. Melzi, M. C. Moioli, P. Cicconi, and T. Formenti (Milano); R. Esposito and C. Mussini (Modena); A. Gori (Monza), N. Abrescia, A. Chirianni, C. M. Izzo, M. De Marco, R. Viglietti, and E. Manzillo (Napoli); C. Ferrari and P. Pizzaferri (Parma); F. Baldelli and G. Camanni (Perugia); G. Magnani and M. A. Ursitti (Reggio Emilia); M. Arlotti and P. Ortolani (Rimini); R. Cauda, M. Andreoni, A. Antinori, G. Antonucci, P. Narciso, V. Tozzi, V. Vullo, A. De Luca, M. Zaccarelli, R. Acinapura, P. De Longis, M. P. Trotta, M. Lichtner, and F. Carletti (Roma); M. S. Mura and G. Madeddu (Sassari); P. Caramello, G. Di Perri, and G. C. Orofino (Torino); E. Raise and F. Ebo (Venezia); and G. Pellizzer and D. Buonfrate (Vicenza).

Nice HIV Cohort (France). Central coordination: C. Pradier, E. Fontas, and C. Caissotti. Participating physicians: P. Dellamonica, L. Bentz, E. Bernard, E. Cua, F. De Salvador- Guillouet, J. Durant, R. Farhad, S. Ferrando, V. Mondain-Miton, I. Perbost, B. Prouvost-Keller, P. Pugliese, V. Rahelinirina, P. M. Roger, and M. Vassallo. Clinical research assistant: E. Baëz.

Swiss HIV Cohort Study (SHCS; Switzerland). P. Francioli (President), M. Battegay, E. Bernasconi, J. Bo"ni, H. Bucher, P. Bürgisser, S. Cattacin, M. Cavassini, R. Dubs, M. Egger, L. Elzi, P. Erb, M. Fischer, M. Flepp, A. Fontana, H. J. Furrer, M. Gorgievski, H. Günthard, B. Hirschel, L. Kaiser, C. Kind, T. Klimkait, U. Lauper, B. Ledergerber, M. Opravil, F. Paccaud, G. Pantaleo, L. Perrin, J.-C. Piffaretti, M. Rickenbach, C. Rudin P. Schmid, J. Schu"pbach, R. Speck, A. Telenti, A. Trkola, P. Vernazza, R. Weber, and S. Yerly.