Trends in Mortality in People With HIV From 1999 through 2020: A Multicohort Collaboration

Abstract

Background

Mortality among people with human immunodeficiency virus (HIV) declined with the introduction of combination antiretroviral therapy. We investigated trends in mortality in people with HIV from 1999 through 2020.

Methods

Data were collected from the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort between January 1999 through January 2015 and the International Cohort Consortium of Infectious Disease (RESPOND) from October 2017 through December 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV, were calculated. Poisson models were used to assess mortality over time.

Results

Among 55 716 participants followed for median 6 years (interquartile range, 3–11), 5263 died (mortality rate [MR], 13.7/1000 person-years of follow-up [PYFU]; 95% confidence interval [CI], 13.4–14.1). Changing mortality was observed: AIDS mortality was most common between 1999–2009 (n = 952; MR, 4.2/1000 PYFU; 95% CI, 4.0–4.5) and non-AIDS–defining malignancy (NADM) between 2010–2020 (n = 444; MR, 2.8/1000 PYFU; 95% CI, 2.5–3.1). In multivariable analysis, all-cause mortality declined (adjusted mortality rate ratio [aMRR], 0.97 per year; 95% CI, .96–.98), mostly 1999–2010 (aMRR, 0.96 per year; 95% CI, .95–.97) but was stable 2011–2020 (aMRR, 1.00 per year; 95% CI, .96–1.05). Mortality due to all known causes except NADM also declined.

Conclusions

Mortality among people with HIV in the D:A:D and/or RESPOND cohorts declined between 1999–2009 and was stable over the period 2010–2020. This decline in mortality was not fully explained by improvements in immunologic–virologic status or other risk factors.

Graphical Abstract

This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/trends-in-mortality-in-people-with-hiv-from-1999-to-2020-a-multi-cohort-collaboration?utm_campaign=tidbitlinkshare&utm_source=IO

mortality, people with HIV, HIV, observational cohort, cohort collaboration

Since the introduction of combination antiretroviral therapy (ART), there has been a steady decline in mortality among people with human immunodeficiency virus (HIV), driven by improvements in virological control, immunological status, and decreased incidence of AIDS [1–4]. Life expectancy among people with HIV is approaching that of the general population across Europe and North America, at least in subgroups with well-controlled HIV; no smoking, drug, or alcohol use; and few comorbidities [5–8]. Furthermore, the relative proportion of deaths due to non-AIDS causes among people with HIV, including cardiovascular disease (CVD), non-AIDS–defining malignancies (NADM), and liver disease, may be increasing [1–4], partly due to people with HIV aging as a population [9]. High prevalence of risk factors associated with mortality is often observed in people with HIV, including smoking; drug and alcohol use [10–15]; higher rates of hypertension, hyperlipidemia, and diabetes mellitus (DM) [16–18]; and coinfection with hepatitis B (HBV) and hepatitis C (HCV) [17, 19].

The Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort collaboration examined deaths from 1999 to 2011 [1], reporting decreased overall mortality and reduced prevalence of AIDS mortality. More recent publications have reported an increase in the proportion of non-AIDS deaths [4, 20–22]. Given the trends of longer life expectancy among people with HIV, understanding recent patterns in mortality and modifiable risk factors is important for shaping future clinical management, systematically monitoring for unexpected trends, and identifying opportunities for interventions to reduce mortality.

We aim to expand on the previous work in the D:A:D cohort [1] by investigating trends in all-cause and cause-specific mortality over more than 20 years (1999–2020) using both the D:A:D and International Cohort Consortium of Infectious Disease (RESPOND) [23] cohort collaborations and rigorously classified causes of death using the Coding Causes of Death in HIV (CoDe) methodology [24]. We also investigated the effect of immunologic–virologic status and additional risk factors on those trends over time and performed stratified analyses to determine whether trends over time are concentrated in earlier or later periods.

METHODS

Study Population and Data Collection

The D:A:D and RESPOND studies used the same underlying methodology and data collection/coordination structure; some cohorts contributed data to both studies. Participants were enrolled from preexisting cohorts and contributed data to D:A:D and/or RESPOND if they fit inclusion criteria, described previously in [23, 25]; of note, ART-naive status is not an inclusion criterion.

The D:A:D study was a collaboration of 11 cohorts that included approximately 50 000 people with HIV across Europe, Australia, and the United States [1, 26]. Participants were recruited during 3 waves, December 1999–April 2001, December 2003–May 2004, and January 2010–December 2010, and followed prospectively until 2016. RESPOND was initiated in 2017 and includes approximately 30 000 people with HIV from 17 cohorts across Europe and Australia, with approximately 3000 new participants added each year [23]. The last year of follow-up was omitted from each cohort to account for delays in mortality reporting, as in previous work [1, 27]. D:A:D data spans from January 1999 through January 2015, and RESPOND data spans from October 2017 through December 2020. Time between the end of D:A:D and the start of RESPOND is not included for participants enrolled in both.

All participants aged ≥18 years at enrollment in RESPOND or D:A:D were eligible for inclusion. RESPOND participants who were missing CD4 count or HIV viral load (HIV-VL) measurement at baseline were excluded from analysis, per RESPOND inclusion criteria [23]. Baseline was defined as the earliest start of prospective follow-up. Loss to follow-up (LTFU) date was imputed after the last clinic visit, that is, 6 months in D:A:D or 2 years in RESPOND, following previous research and different standards of care over time [1, 27, 28]. Follow-up ended at the earliest of dropout, death, imputed LTFU date, or administrative censoring. Participants with unknown sex/gender were excluded due to very low numbers (n <10); no deaths were observed in this group.

Outcome Classification

Causes of death were classified using CoDe [24] from 2004 onward; mortality before 2004 was classified using International Classification of Diseases, Tenth Revision, codes and synchronized with CoDe categories [1]. CoDe forms were completed in real time by contributing clinical centers and adjudicated by clinicians at the D:A:D/RESPOND coordinating center; missing information was extensively queried. Individual CoDe causes were grouped into the following specific categories: AIDS (including AIDS-defining malignancies), NADM (all cancers other than AIDS-defining malignancies [29], hepatocellular carcinoma, nonmalignant melanoma skin cancers, and precancers), CVD (myocardial infarction, stroke, or other heart or vascular causes), or liver-related (any liver disease including hepatocellular carcinoma) [1]. All other known causes were grouped into the “other” category. Cases where mortality was recorded with insufficient information for classification are assigned unknown/missing cause. Clinical centers with no reported cause for at least 20% of deaths were excluded from analysis.

Baseline Characteristics

Baseline characteristics were defined at the start of prospective follow-up and described for RESPOND and D:A:D and between included and excluded participants. Characteristics of interest included age, sex/gender, race/ethnicity, geographic region, HIV exposure group, smoking status, HIV-VL, nadir and current CD4 count, ART exposure (naive vs ever exposed), HBV, HCV, body mass index (BMI), hypertension, and DM. European geographic regions were defined as in previous research [19, 27]. The demographic variable sex/gender was not collected consistently and includes gender information where available, otherwise sex.

Baseline CD4 count and HIV-VL were defined at the measurement closest to baseline within 1 year prior or, if unavailable, within 3 months post. Current CD4 count and HIV-VL were categorized in the composite measure of immunologic–virologic status: poor (CD4 count ≤350 cells/mm³ and HIV-VL >200 copies/mm³), good (CD4 count ≥500 cells/mm³ and HIV-VL <200 copies/mm³), or intermediate (remaining combinations) [30]. Definitions of HCV, HBV, smoking status, DM, hypertension, and BMI can be found in the Supplementary Material. Risk factors missing information were categorized as unknown.

Mortality Analysis

Age-standardized all-cause and cause-specific mortality rates were calculated for periods of 2 calendar years. Standardization used the age distribution of the entire follow-up period, with 10-year groups from <30, 30–39… to ≥80, using Dobson's approach to calculate confidence intervals (CIs) [31–33]. The proportion of deaths comprised by each cause was calculated for 2-year periods and within each cohort. Distribution of person-time in immunologic–virologic strata and ART experienced vs ART naive, respectively, were calculated over the entire follow-up period and for each calendar year. χ² tests were performed to assess distributions of causes of death and immunologic–virologic status over the entire period, 1999–2009, and 2010–2020. Median and interquartile range (IQR) for age at death were calculated for each calendar year of follow-up.

Risk factors for all-cause and cause-specific mortality were assessed using univariate and multivariable Poisson regression with robust standard errors [34, 35]. Risk factors were time-updated with the last observation carried forward. To investigate the impact of improved immunologic–virologic status over time, partially adjusted multivariable analyses included time-updated age group, calendar year, cohort study (D:A:D vs RESPOND), and time-updated immunologic–virologic status. Fully adjusted analyses, following Smith et al 2014 [1], included those same risk factors with the addition of the baseline variables sex/gender, race/ethnicity, and HIV exposure group and the time-updated variables HBV and HCV status, smoking status, DM, hypertension, and BMI. To investigate time trends in different periods, analyses were stratified by early (1999–2009) and late (2010–2020) periods. Sensitivity analysis was performed with RESPOND LTFU imputed after 6 months to ensure that the longer LTFU period did not bias results. Crude rates of LTFU were calculated over the entire follow-up period and within early (1999–2009) and late (2010–2020) periods. Analyses were performed using R version 4.2.2 [36–38].

RESULTS

Of 61 649 participants, 5933 (all from RESPOND) were excluded from analysis: 6 (<1%) with unknown sex/gender, 4601 (78%) from 4 contributing centers (23.5%) wherein more than 20% of recorded deaths were missing causes, and 1326 (22%) who did not meet the RESPOND inclusion criteria due to missing CD4 or HIV-VL measurement within the period 1 year prior or 3 months after baseline. See Supplementary Table 1 for baseline characteristics of included and excluded participants.

A total of 55 716 participants were included in the analysis with 382 828 person-years of follow-up (PYFU; median, 6.00 years; IQR, 3.25–11.00). D:A:D contributed 40 940 participants and 345 950 PYFU (median, 8.25 years; IQR, 4.67–12.76), and RESPOND contributed 14 992 participants and 36 878 PYFU (median, 3.25 years; IQR, 1.25–3.25), with 216 participants in both. In both cohorts, most participants were male and the most frequent HIV exposure group was men who have sex with men (Table 1). Participants in RESPOND were slightly older at baseline (median, 46 vs 38 years) and had higher nadir CD4 counts (median, 580 vs 330 cells/mm³).

Table 1.

Baseline Participant Characteristics

Baseline Characteristic		All Participants (n = 55 716)a	D:A:D (n = 40 940)a,b	RESPOND (n = 14 776)a
Age, median (IQR), y		39 (33–48)	38 (32–45)	46 (37–54)
Baseline date, median (IQR)		2004–05–10 (2000–08–11, 2017–10–01)	2001–12–13 (2000–06–14, 2005–07–26)	2017–10–01 (2017–10–01, 2018–10–01)
Sex/Gender	Male	41562 (74.6%)	30348 (74.1%)	11214 (75.9%)
	Female	14123 (25.3%)	10588 (25.9%)	3535 (23.9%)
	Transgender	31 (< 0.1%)	4 (<0.1%)	27 (0.2%)
Ethnicity	White	29976 (53.8%)	18927 (46.2%)	11049 (74.8%)
	Other	6856 (12.3%)	4972 (12.1%)	1884 (12.8%)
	Prohibitedc	17813 (32.0%)	16541 (40.4%)	1272 (8.6%)
	Unknown	1071 (1.9%)	500 (1.2%)	571 (3.9%)
Geographic region	Central West Europe	21879 (39.3%)	14659 (35.8%)	7220 (48.9%)
	Central East Europe	1829 (3.3%)	951 (2.3%)	878 (5.9%)
	Eastern Europe	2448 (4.4%)	1544 (3.8%)	904 (6.1%)
	Northern Europe	16058 (28.8%)	14254 (34.8%)	1804 (12.2%)
	Southern Europe	9853 (17.7%)	5905 (14.4%)	3948 (26.7%)
	Australia	597 (1.1%)	575 (1.4%)	22 (0.1%)
	United States	3052 (5.5%)	3052 (7.5%)
Human immunodeficiency virus exposure group	Men who have sex with men	24735 (44.4%)	18116 (44.3%)	6619 (44.8%)
	Injection drug use	8555 (15.4%)	6346 (15.5%)	2209 (14.9%)
	Heterosexual contact	18129 (32.5%)	13085 (32.0%)	5044 (34.1%)
	Other/Unknown	4297 (7.7%)	3393 (8.3%)	904 (6.1%)
CD4 nadir, median (IQR), cells/mm3		390 (220, 589)d	330 (181, 500)d	580 (399.95, 770)
Immunologic–virologic status	Poor	12226 (21.9%)	11915 (29.1%)	311 (2.1%)
	Intermediate	25022 (44.9%)	20672 (50.5%)	4350 (29.4%)
	Good	16665 (29.9%)	6550 (16%)	10115 (68.5%)
	Unknown	1803 (3.2%)	1803 (4.4%)	-
ART history	ART naive	15416 (27.7%)	15150 (37.0%)	266 (1.8%)
	Ever exposed	40300 (72.3%)	25790 (63.0%)	14510 (98.2%)
Hepatitis C	Positive	8372 (15.0%)	7026 (17.2%)	1346 (9.1%)
	Negative	34906 (62.6%)	24201 (59.1%)	10705 (72.4%)
	Negative (resolved)	2816 (5.1%)	418 (1%)	2398 (16.2%)
	Unknown	9622 (17.3%)	9295 (22.7%)	327 (2.2%)
Hepatitis B	Positive	2434 (4.4%)	2009 (4.9%)	425 (2.9%)
	Negative	45577 (81.8%)	31406 (76.7%)	14171 (95.9%)
	Unknown	7705 (13.8%)	7525 (18.4%)	180 (1.2%)
Diabetes mellitus	Yes	2409 (4.3%)	1426 (3.5%)	983 (6.7%)
	No	34750 (62.4%)	21350 (52.1%)	13400 (90.7%)
	Unknown	18557 (33.3%)	18164 (44.4%)	393 (2.7%)
Hypertension	Yes	7710 (13.8%)	2293 (5.6%)	5417 (36.7%)
	No	30942 (55.5%)	23064 (56.3%)	7878 (53.3%)
	Unknown	17064 (30.6%)	15583 (38.1%)	1481 (10.0%)
Body mass index, kg/m2	<18	2561 (4.6%)	2072 (5.1%)	489 (3.3%)
	18 to <25	29965 (53.8%)	23202 (56.7%)	6763 (45.8%)
	≥25 to <30	11512 (20.7%)	7576 (18.5%)	3936 (26.6%)
	≥30	3289 (5.9%)	1871 (4.6%)	1418 (9.6%)
	Unknown	8389 (15.1%)	6219 (15.2%)	2170 (14.7%)
Smoking history	Never	13270 (23.8%)	9566 (23.4%)	3704 (25.1%)
	Former	6126 (11.0%)	3423 (8.4%)	2703 (18.3%)
	Current	19780 (35.5%)	14447 (35.3%)	5333 (36.1%)
	Unknown	16540 (29.7%)	13504 (33.0%)	3036 (20.5%)

Abbreviation: ART, antiretroviral therapy; D:A:D, Data Collection on Adverse events of Anti-HIV Drugs cohort; IQR, interquartile range; RESPOND, International Cohort Consortium of Infectious Disease.

^an (%) unless otherwise noted.

^bD:A:D includes participants enrolled in both D:A:D and RESPOND.

^cParticipants from countries where collection of race or ethnicity is prohibited.

^dCD4 nadir unknown for 312 participants in D:A:D cohort (0.8% of D:A:D cohort, 0.5% of total).

During follow-up, 5263 participants (9.4%) died (crude mortality rate [MR], 13.7/1000 PYFU; 95% CI, 13.4–14.1). Overall, the most common specific cause of death was AIDS (n = 1170; crude MR, 3.1/1000 PYFU; 95% CI, 2.9–3.2), driven by higher mortality between 1999 and 2009, where AIDS was the leading cause of death (n = 952; crude MR, 4.2/1000 PYFU; 95% CI, 4.0–4.5). Between 2010 and 2020, NADM was the leading specific cause of death (n = 444; crude MR, 2.8/1000 PYFU; 95% CI, 2.5–3.1). See Table 2 for all-cause and cause-specific crude mortality rates overall and stratified by period. A large proportion of deaths were grouped into the “other” category; the most common causes were bacterial infection (n = 294), followed by substance use (n = 166; Supplementary Table 2).

Table 2.

Cause-Specific Crude Mortality Rate per 1000 Person-Years (95% Confidence Interval) of Follow-up by Time Period

Cause of Death	Pooled		1999 Through 2009		2010 Through 2020
	n	MR (95% CI)	n	MR (95% CI)	n	MR (95% CI)
AIDS	1170	3.1 (2.9–3.2)	952	4.2 (4.0–4.5)	218	1.4 (1.2–1.6)
Cardiovascular disease	513	1.3 (1.2–1.5)	334	1.5 (1.3–1.7)	179	1.1 (1.0–1.3)
Liver-related	622	1.6 (1.5–1.8)	444	2.0 (1.8–2.2)	178	1.1 (1.0–1.3)
Non-AIDS–defining malignancy	949	2.5 (2.3–2.6)	505	2.3 (2.1–2.5)	444	2.8 (2.5–3.1)
Other	1499	3.9 (3.7–4.1)	946	4.2 (4.0–4.5)	553	3.5 (3.2–3.8)
Unknown/Missing	510	1.3 (1.2–1.5)	226	1.0 (.9–1.1)	284	1.8 (1.6–2.0)
All-cause	5263	13.7 (13.4–14.1)	3407	15.2 (14.7–15.7)	1856	11.7 (11.2–12.2)

Abbreviations: CI, confidence interval; MR, mortality rate.

A total of 8890 participants were lost to follow-up (16.0%). The crude rate of LTFU was 23.2 per 1000 PYFU (95% CI, 22.7–23.7) over the entire period, 27.4 per 1000 PYFU (95% CI, 26.8–28.1) between 1999 and 2009, and 17.2 per 1000 PYFU (95% CI, 16.6–17.9) between 2010 and 2020.

The relative proportion of AIDS mortality decreased over time from 31.0% in 1999–2000 to 5.3% in 2019–2020, as did liver-related mortality (15.3% to 5.6%), while the proportion of NADM mortality increased from 8.9% to 23.0% (Figure 1). These changing proportions were statistically significant over the full follow-up period and in both the earlier and later periods (all P < .001). Over the entire follow-up period, most person-time was under good immunologic–virologic status (43.7%) or intermediate (45.0%), with only 9.3% under poor and 1.9% unknown. The proportion of person-time under good immunologic–virologic status increased from 19.0% in 1999 to 73.4% in 2020 (P < .001; Figure 2). Over the entire follow-up period, 12.1% of person-time was ART-naive, with 74.6% of ART-naive follow-up time in the period 1999–2009. Median age at death increased over time, from 42 years (IQR, 37–49) in 1999–2000 to 58 years (IQR, 51–66) in 2019–2020.

Figure 1.

Distribution of causes of death over time. Causes of death are categorized by CoDe form as outlined in the Methods section. x-axis: periods from 1999 through 2020, grouped into 2-year periods. y-axis: proportion of all deaths in each 2-year period comprised by each CoDe category. Bars are color-coded by CoDe categories, in the same order, as shown in the legend. No data were collected between February 2015 and October 2017. Abbreviations: CoDe, Coding Causes of Death in human immunodeficiency virus; CVD, cardiovascular disease; NADM, non-AIDS–defining malignancy.

Figure 2.

Immunologic–virologic status over time. Immunologic–virologic status is time-updated and categorized as poor (CD4 count ≤350 cells/mm³ and human immunodeficiency virus viral load [HIV-VL] >200 copies/mm³), good (CD4 count ≥500 cells/mm³ and HIV-VL <200 copies/mm³), or intermediate (remaining combinations). x-axis: years from 1999 through 2020. y-axis: proportion of person-time under follow-up in each year comprised by each immunologic–virologic category. Bars are color-coded by immunologic–virologic categories, in the same order, as shown in the legend. No data were collected between February 2015 and October 2017. Abbreviation: PYFU, person-years of follow-up.

Age-standardized mortality rates show a decline in all-cause mortality (Figure 3A) from 19.0 deaths per 1000 PYFU (95% CI, 16.2–22.1) in 1999–2000 to 10.1 per 1000 PYFU (95% CI, 9.0–11.4) in 2019–2020. Age-standardized cause-specific mortality rates also declined for AIDS, CVD, liver-related, and other causes but not for NADM or unknown/missing causes (Figure 3B).

Figure 3.

A, Age-standardized all-cause mortality rates over time. Age-standardized all-cause mortality rates were calculated for periods of 2 calendar years. Age standardization was estimated using the age distribution of the entire follow-up period, with ages grouped into roughly 10-year groups from <30, 30–39, 40–49… to ≥80, using Dobson's approach to calculate confidence intervals. x-axis: 2-year periods from 1999 through 2020. y-axis: age-standardized mortality rates per 1000 person-years of follow-up with 95% confidence intervals. No data were collected between February 2015 and October 2017. B, Age-standardized cause-specific mortality rates over time. Age-standardized cause-specific mortality rates were calculated for periods of 2 calendar years. Age standardization was estimated using the age distribution of the entire follow-up period, with ages grouped into roughly 10-year groups from <30, 30–39, 40–49… to ≥80, using Dobson's approach to calculate confidence intervals. x-axis: 2-year periods from 1999 through 2020. y-axis: age-standardized mortality rates per 1000 person-years of follow-up with 95% confidence intervals. No data were collected between February 2015 and October 2017. Abbreviations: CVD, cardiovascular disease; MR, mortality rate; NADM, non-AIDS–defining malignancy; PYFU, person-years of follow-up.

In multivariable analysis, all-cause mortality decreased over time (fully adjusted mortality rate ratio [aMRR], 0.97 per year; 95% CI, .96–.98; Table 3). Fully adjusted multivariable Poisson analyses stratified by periods indicate that, after controlling for covariates, all-cause mortality declined between 1999 and 2009 (aMRR, 0.96 per year; 95% CI, .95–.97) but was stable between 2010 and 2020 (aMRR, 1.00 per year; 95% CI, .96–1.05). For cause-specific mortality (Table 3), fully adjusted models showed declining mortality rates over time for AIDS, CVD, liver-related, and other causes but not for NADM. Results were consistent in sensitivity analysis with a 6-month LTFU period used for both cohorts.

Table 3.

Effect of Calendar Year in Poisson Regression: Mortality Rate Ratios and 95% Confidence Intervals per Calendar Year

Cause of Death		Crude Model	Partial Adjusteda	Fully Adjustedb
All Cause	Full period	0.97 (0.97–0.98)	0.99 (0.98–0.99)	0.97 (0.96–0.98)
	1999–2009	0.95 (0.94–0.96)	0.98 (0.97–0.99)	0.96 (0.95–0.97)
	2010–2020	1.02 (1–1.04)	1.01 (0.97–1.06)	1 (0.96–1.05)
AIDS	Full period	0.89 (0.88–0.9)	0.96 (0.95–0.98)	0.95 (0.94–0.97)
	1999–2009	0.91 (0.89–0.93)	0.98 (0.96–1)	0.97 (0.95–0.99)
	2010–2020	0.9 (0.85–0.96)	0.87 (0.75–1.02)	0.86 (0.74–1)
Cardiovascular disease	Full period	0.96 (0.95–0.98)	0.91 (0.89–0.94)	0.88 (0.86–0.91)
	1999–2009	0.91 (0.88–0.94)	0.89 (0.86–0.92)	0.85 (0.82–0.89)
	2010–2020	1.01 (0.96–1.06)	0.88 (0.76–1.01)	0.86 (0.74–0.99)
Liver-related	Full period	0.93 (0.92–0.95)	0.98 (0.96–1)	0.95 (0.93–0.97)
	1999–2009	0.92 (0.89–0.94)	0.95 (0.92–0.98)	0.93 (0.89–0.96)
	2010–2020	0.91 (0.86–0.97)	0.96 (0.83–1.1)	0.93 (0.8–1.07)
Non-AIDS–defining malignancy	Full period	1.03 (1.02–1.04)	1.03 (1.01–1.05)	1.01 (0.99–1.03)
	1999–2009	1.04 (1.01–1.06)	1.03 (1–1.06)	1 (0.97–1.03)
	2010–2020	1.03 (1–1.06)	1.08 (0.98–1.18)	1.07 (0.98–1.17)
Other	Full period	0.98 (0.97–0.99)	0.99 (0.98–1.01)	0.98 (0.96–0.99)
	1999–2009	0.95 (0.93–0.97)	0.97 (0.95–0.99)	0.96 (0.94–0.98)
	2010–2020	0.99 (0.96–1.02)	1.03 (0.95–1.11)	1.02 (0.94–1.11)
Unknown/Missing	Full period	1.09 (1.07–1.11)	1.05 (1.02–1.07)	1.05 (1.02–1.08)
	1999–2009	1.04 (1–1.08)	1.06 (1.02–1.11)	1.07 (1.02–1.12)
	2010–2020	1.18 (1.14–1.23)	1.12 (1–1.26)	1.13 (1.01–1.27)

Abbreviations: D:A:D, Data Collection on Adverse events of Anti-HIV Drugs cohort; RESPOND, International Cohort Consortium of Infectious Disease.

^aPartially adjusted model includes current age group, calendar year, cohort study (D:A:D vs RESPOND), and current immunologic–virologic status as risk factors.

^bFully adjusted model includes all risk factors in partially adjusted models, as well as sex/gender, race/ethnicity, human immunodeficiency virus exposure group, current hepatitis B virus and hepatitis C virus status, current smoking status, diabetes, hypertension, and body mass index.

Of note, in fully adjusted multivariable analysis, the decline over time in AIDS mortality was attenuated, but not nullified, by the inclusion of immunologic–virologic status and other risk factors. Unlike other causes, the decline in CVD mortality was not attenuated by adjustment; the magnitude of the effect of calendar year increased after adjustment (crude MRR, 0.96 per year; 95% CI, .95–.98 and fully adjusted MRR, 0.88 per year; 95% CI, .86–.91), indicating that there are other risk factors not included in the model that account for the decline in CVD mortality over time.

DISCUSSION

Age-standardized rates of all-cause mortality in the D:A:D and RESPOND cohorts declined over the period from 1999 through 2020, mainly between 1999 and 2009, with more stable rates between 2010 and 2020. These results expand on the decline observed in the D:A:D study between 1999 and 2011 [1], adding 9 years of follow-up, and in accord with other recent studies that investigated mortality rates among people with HIV [2, 21, 22].

Another large international cohort collaboration of people with HIV (ART-CC) recently reported on trends in mortality over a similar period [22]. Both studies observed declines in mortality over the last 2 decades and changes in the leading cause, with decreases in AIDS-related mortality and increases in the proportion of mortality due to NADM. While the overall pattern was similar, we observed a slightly higher crude mortality rate (13.7 per 1000 PYFU; 95% CI, 13.4–14.1) than in the ART-CC (11.1 per 1000 PYFU; 95% CI, 10.9–11.3), likely due to differences in the 2 populations. The D:A:D and RESPOND cohorts predominately include participants from Europe, including Eastern Europe, where rates of mortality among people with HIV are higher [39]. In contrast, the ART-CC includes a higher proportion of North American cohorts that reported larger declines in mortality rates compared with cohorts in Europe [22]. The current analysis also contains nearly twice the proportion of people with injection drug use as their HIV exposure risk or who were HCV-positive at baseline, as well as a sizable proportion of follow-up time from individuals who were ART-naive (12.1%), further distinguishing the cohorts in mortality risk factors [27, 28, 40, 41]. While we show a concentrated decline in mortality between 1999 and 2009 and stable rates between 2010 and 2020, changes in mortality rate in different time periods were not specifically investigated by Trickey et al [22].

The general shift from AIDS to non-AIDS mortality likely reflects changing treatment guidelines with earlier start of more efficient and well-tolerated ART [28, 42], leading to improved immunologic–virologic status and less inflammation, as well as higher rates of cancer among an aging population. The attenuation of the effect of calendar year on AIDS mortality after adjustment for risk factors, especially immunologic–virologic status, indicates that the included covariates were strongly associated with declining AIDS mortality but do not fully explain this decline.

Age-standardized cause-specific mortality rates for AIDS, CVD, liver-related, and “other” deaths declined over time. This was likely due to better immunologic–virologic control; earlier start of ART; availability of improved, less toxic ART regimens; and the associated reduction of risk for both AIDS and non-AIDS outcomes, as well as management of associated risk factors [28, 43]. These decreased cause-specific mortality rates also contribute to the larger proportion of NADM mortality in later periods.

The observed stable rates of NADM mortality, unlike other causes of death, differ from those of Trickey et al [22] who found a decline in NADM mortality. In addition to differences in cohort makeup, age-standardized incidence of NADM increased over a similar time period in the D:A:D and RESPOND cohorts [44], which may explain the different patterns and supports recent literature arguing for more focused research on NADM among people with HIV [45, 46]. Furthermore, cancer causes are multifactorial, and many of these causes are not captured in these cohort studies. Median age at death in cohort studies is not related to mortality rates and cannot be interpreted as life expectancy [47], but declining age-standardized mortality rates over time likely indicate improved quality of care.

Strengths of our study include prospective collection of clinical data in a large, international cohort consortium setting. Causes of death were classified using the CoDe protocol, which has been shown to be a robust method of mortality classification among people with HIV, with less risk of misclassification than using death registry data [24]. The combination of 2 large cohort collaborations sharing common data structure is another strength, as it allows for more than 20 years of follow-up and includes more than 55 000 participants [23–25, 48]. We included several risk factors and clinical conditions that are highly associated with mortality, namely, smoking, BMI, HBV, DM, and hypertension. Interesting avenues for future research would be more complex and outcome-specific associative models of cause-specific mortality.

One limitation of this study is uncollected or inconsistently collected data, including drug and alcohol use and socioeconomic information, which would provide important risk factors for mortality, especially in a heterogeneous, international cohort. This information may have helped to further explain some of the changes observed over time. Data reporting also varied between cohorts, for example, more of the person-time under follow-up in the D:A:D cohort is missing immunologic–virologic status, and a greater proportion of deaths have unknown or missing causes in RESPOND (29.4%) than in D:A:D (7.8%). Individual cohorts are queried extensively for missing information about the underlying causes of death. Anecdotally, increased migration and specialist care at other sites, including in private clinics, has presented contributing clinics with difficulties in obtaining information regarding underlying cause of death in recent years. In addition, cause of death reporting may have been impacted during the coronavirus disease 2019 period. These issues complicate interpretations of trends over time. Further, the exclusion of centers with inadequate cause-of-death reporting primarily affected participants with good immunologic–virologic status (Supplementary Table 1). This may have led to an overestimation of mortality in the later follow-up period and a more conservative estimate of the trends of declining mortality. While unobserved mortality could bias results, rates of LTFU were lower between 2010 and 2020 compared with between 1999 and 2009; any resulting bias would push the observed results toward the null. Last, findings within this population are not externally generalizable to other settings, as these cohort collaborations are comprised largely of white males in Europe.

CONCLUSIONS

Mortality rates among people with HIV in the D:A:D/RESPOND cohorts decreased between 1999 and 2009 and were stable between 2010 and 2020. While mortality due to AIDS, CVD, and liver-related causes declined, NADM mortality remained stable. Immunologic–virologic status improved significantly over the study period and contributed to the decline in mortality rates. However, improved immunologic–virologic status and other mortality risk factors did not fully explain the reduction in all-cause or cause-specific mortality rates.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author Contributions. All authors had full access to the data in the study and had final responsibility for the decision to submit for publication. E. T. and J. R. accessed and verified the data. E. T., L. R., A. P. M., A. M., C. S., L. P., and J. R. conceptualized the analyses. L. R., A. M., H. G., A. d’A. M., C. P., F. B., S. D. W., W. E.-S., B. N., N. J., C. S., J. L., and L. P. were involved in project administration and steering committees. E. T. wrote the original draft of the manuscript. All authors contributed to review and editing.

Members of the cohort consortiums

D:A:D

D:A:D Participating Cohorts:

Aquitaine, France; Community Programs for Clinical Research on AIDS (CPCRA), USA; Nice Cohort, France; AIDS Therapy Evaluation in the Netherlands (ATHENA), The Netherlands; EuroSIDA, Europe; Swiss HIV Cohort Study (SHCS), Switzerland; Australian HIV Observational Database (AHOD), Australia; HIV Biverknings Undersökning (HIV-BIVUS), Sweden; St. Pierre Brussels Cohort, Belgium; Barcelona Antiretroviral Surveillance Study (BASS), Spain; The ICONA Foundation, Italy

D:A:D Steering Committee: Names marked with *, co-chairs with ¢

Cohort PIs: W. El-Sadr* (CPCRA), G. Calvo* (BASS), F. Bonnet and F. Dabis* (Aquitaine), O. Kirk* and A. Mocroft* (EuroSIDA), M. Law* (AHOD), A. d’Arminio Monforte* (ICONA), L. Morfeldt* (HIV-BIVUS), C. Pradier* (Nice), P. Reiss* (ATHENA), R. Weber* (SHCS), S. De Wit* (Brussels)

Cohort coordinators and data managers: A. Lind-Thomsen (coordinator), R. Salbøl Brandt, M. Hillebreght, S. Zaheri, F. W. N. M. Wit (ATHENA), A. Scherrer, F. Schöni-Affolter, M. Rickenbach (SHCS), A. Tavelli, I. Fanti (ICONA), O. Leleux, J. Mourali, F. Le Marec, E. Boerg (Aquitaine), E. Thulin, A. Sundström (HIV-BIVUS), G. Bartsch, G. Thompsen (CPCRA), C. Necsoi, M. Delforge (Brussels), E. Fontas, C. Caissotti, K. Dollet (Nice), S. Mateu, F. Torres (BASS), K. Petoumenos, A. Blance, R. Huang, R. Puhr (AHOD), K. Grønborg Laut, D. Kristensen (EuroSIDA)

Statisticians: C. A. Sabin*¢, A. N. Phillips*, D. A. Kamara, C. J. Smith, A. Mocroft*

D:A:D coordinating office: C. I. Hatleberg, A. Lind-Thomsen, R. S. Brandt, D. Raben, C. Matthews, A. Bojesen, A. L. Grevsen, J. D. Lundgren*, L. Ryom*¢

Member of the D:A:D Oversight Committee: B. Powderly*, N. Shortman*, C. Moecklinghoff*, G. Reilly*, X. Franquet*

D:A:D working group experts:

Kidney: L. Ryom*¢, A. Mocroft*, O. Kirk *, P. Reiss*, C. Smit, M. Ross, C. A. Fux, P. Morlat, E. Fontas, D. A. Kamara, C. J. Smith, J. D. Lundgren *

Mortality: C. J. Smith, L. Ryom*¢, C. I. Hatleberg, A. N. Phillips*, R. Weber*, P. Morlat, C. Pradier*, P. Reiss*, F. W. N. M. Wit, N. Friis-Møller, J. Kowalska, J. D. Lundgren*

Cancer: C. A. Sabin*¢, L. Ryom*¢, C. I. Hatleberg, M. Law*, A. d'Arminio Monforte*, F. Dabis*, F. Bonnet*, P. Reiss*, F. W. N. M. Wit, C. J. Smith, D. A. Kamara, J. Bohlius, M. Bower, G. Fätkenheuer, A. Grulich, J. D. Lundgren*¢

External endpoint reviewers: A. Sjøl (CVD), P. Meidahl (oncology), J. S. Iversen (nephrology)

Funding: By a grant (grantDNRF126) from the Danish National Research Foundation (CHIP & PERSIMUNE); “Oversight Committee for The Evaluation of Metabolic Complications of HAART” with representatives from academia, patient community, FDA, EMA, and a consortium of AbbVie, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, and Janssen Pharmaceuticals.

The members of the 11 cohorts at the time of D:A:D conclusion were as follows:

ATHENA (AIDS Therapy Evaluation Project Netherlands):

Central coordination: P. Reiss*, S. Zaheri, M. Hillebregt, F. W. N. M. Wit;

Clinical Centers (¤ denotes site coordinating physician) Academic Medical Centre of the University of Amsterdam: J. M. Prins¤, T. W. Kuijpers, H. J. Scherpbier, J. T. M. van der Meer, F. W. N. M. Wit, M. H. Godfried, P. Reiss, T. van der Poll, F. J. B. Nellen, S. E. Geerlings, M. van Vugt, D. Pajkrt, J. C. Bos, W. J. Wiersinga, M. van der Valk, A. Goorhuis, J. W. Hovius, J. van Eden, A. Henderiks, A. M. H. van Hes, M. Mutschelknauss, H. E. Nobel, F. J. J. Pijnappel, S. Jurriaans, N. K. T. Back, H. L. Zaaijer, B. Berkhout, M. T. E. Cornelissen, C. J. Schinkel, X. V. Thomas. Admiraal De Ruyter Ziekenhuis, Goes: M. van den Berge, A. Stegeman, S. Baas, L. Hage de Looff, D. Versteeg. Catharina Ziekenhuis, Eindhoven: M. J. H. Pronk¤, H. S. M. Ammerlaan, E. S. de Munnik. A. R. Jansz, J. Tjhie, M. C. A. Wegdam, B. Deiman, V. Scharnhorst. Emma Kinderziekenhuis: A. van der Plas, A. M. Weijsenfeld. Erasmus MC, Rotterdam: M. E. van der Ende¤, T. E. M. S. de Vries-Sluijs, E. C. M. van Gorp, C. A. M. Schurink, J. L. Nouwen, A. Verbon, B. J. A. Rijnders, H. I. Bax, M. van der Feltz, N. Bassant, J. E. A. van Beek, M. Vriesde, L. M. van Zonneveld, A. de Oude-Lubbers, H. J. van den Berg-Cameron, F. B. Bruinsma-Broekman, J. de Groot, M. de Zeeuw- de Man, C. A. B. Boucher, M. P. G Koopmans, J. J. A van Kampen, S. D. Pas. Erasmus MC–Sophia, Rotterdam: G. J. A. Driessen, A. M. C. van Rossum, L. C. van der Knaap, E. Visser. Flevoziekenhuis, Almere: J. Branger¤, A. Rijkeboer-Mes, C. J. H. M. Duijf-van de Ven. HagaZiekenhuis, Den Haag: E. F. Schippers¤, C. van Nieuwkoop, J. M. van IJperen, J. Geilings, G. van der Hut, P. F. H. Franck. HIV Focus Centrum (DC Klinieken): A. van Eeden¤, W. Brokking, M. Groot, L. J. M. Elsenburg, M. Damen, I. S. Kwa. Isala, Zwolle: P. H. P. Groeneveld¤, J. W. Bouwhuis, J. F. van den Berg, A. G. W. van Hulzen, G. L. van der Bliek, P. C. J. Bor, P. Bloembergen, M. J. H. M. Wolfhagen, G. J. H. M. Ruijs. Leids Universitair Medisch Centrum, Leiden: F. P. Kroon¤, M. G. J. de Boer, M. P. Bauer, H. Jolink, A. M. Vollaard, W. Dorama, N. van Holten, E. C. J. Claas, E. Wessels. Maasstad Ziekenhuis, Rotterdam: J. G. den Hollander¤, K. Pogany, A. Roukens, M. Kastelijns, J. V. Smit, E. Smit, D. Struik-Kalkman, C. Tearno, M. Bezemer, T. van Niekerk, O. Pontesilli. Maastricht UMC+, Maastricht: S. H. Lowe¤, A. M. L. Oude Lashof, D. Posthouwer, R. P. Ackens, J. Schippers, R. Vergoossen, B. Weijenberg-Maes, I. H. M. van Loo, T. R. A. Havenith. MCH-Bronovo, Den Haag: E. M. S. Leyten¤, L. B. S. Gelinck, A. van Hartingsveld, C. Meerkerk, G. S. Wildenbeest, J. A. E. M. Mutsaers, C. L. Jansen. MC Slotervaart, Amsterdam: J. W. Mulder, S. M. E. Vrouenraets, F. N. Lauw, M. C. van Broekhuizen, H. Paap, D. J. Vlasblom, P. H. M. Smits. MC Zuiderzee, Lelystad: S. Weijer¤, R. El Moussaoui, A. S. Bosma. Medisch Centrum Leeuwarden, Leeuwarden: M. G. A. van Vonderen¤, D. P. F. van Houte, L. M. Kampschreur, K. Dijkstra, S. Faber, J. Weel. Medisch Spectrum Twente, Enschede: G. J. Kootstra¤, C. E. Delsing, M. van der Burg-van de Plas, H. Heins, E. Lucas. Noorwest Ziekenhuisgroep, Alkmaar: W. Kortmann¤, G. van Twillert¤, J. W. T. Cohen Stuart, B. M. W. Diederen, D. Pronk, F. A. van Truijen-Oud, W. A. van der Reijden, R. Jansen. OLVG, Amsterdam: K. Brinkman¤, G. E. L. van den Berk, W. L. Blok, P. H. J. Frissen, K. D. Lettinga, W. E. M. Schouten, J. Veenstra, C. J. Brouwer, G. F. Geerders, K. Hoeksema, M. J. Kleene, I. B. van der Meché, M. Spelbrink, H. Sulman, A. J. M. Toonen, S. Wijnands, M. Damen, D. Kwa, E. Witte. Radboudumc, Nijmegen: P. P. Koopmans, M. Keuter, A. J. A. M. van der Ven, H. J. M. ter Hofstede, A. S. M. Dofferhoff, R. van Crevel, M. Albers, M. E. W. Bosch, K. J. T. Grintjes-Huisman, B. J. Zomer, F. F. Stelma, J. Rahamat-Langendoen, D. Burger. Rijnstate, Arnhem: C. Richter¤, E. H. Gisolf, R. J. Hassing, G. ter Beest, P. H. M. van Bentum, N. Langebeek, R. Tiemessen, C. M. A. Swanink. Spaarne Gasthuis, Haarlem: S. F. L. van Lelyveld¤, R. Soetekouw, N. Hulshoff, L. M. M. van der Prijt, J. van der Swaluw, N. Bermon, W. A. van der Reijden, R. Jansen, B. L. Herpers, D. Veenendaal. Medisch Centrum Jan van Goyen, Amsterdam: D. W. M. Verhagen, M. van Wijk. St Elisabeth Ziekenhuis, Tilburg: M. E. E. van Kasteren¤, A. E. Brouwer, B. A. F. M. de Kruijf-van de Wiel, M. Kuipers, R. M. W. J. Santegoets, B. van der Ven, J. H. Marcelis, A. G. M. Buiting, P. J. Kabel. Universitair Medisch Centrum Groningen, Groningen: W. F. W. Bierman¤, H. Scholvinck, K. R. Wilting, Y. Stienstra, H. de Groot-de Jonge, P. A. van der Meulen, D. A. de Weerd, J. Ludwig-Roukema, H. G. M. Niesters, A. Riezebos-Brilman, C. C. van Leer-Buter, M. Knoester. Universitair Medisch Centrum Utrecht, Utrecht: A. I. M. Hoepelman¤, T. Mudrikova, P. M. Ellerbroek, J. J. Oosterheert, J. E. Arends, R. E. Barth, M. W. M. Wassenberg, E. M. Schadd, D. H. M. van Elst-Laurijssen, E. E. B. van Oers-Hazelzet, S. Vervoort, M. van Berkel, R. Schuurman, F. Verduyn-Lunel, A. M. J. Wensing. VUmc, Amsterdam: E. J. G. Peters¤, M. A. van Agtmael, M. Bomers, J. de Vocht, M. Heitmuller, L. M. Laan, A. M. Pettersson, C. M. J. E. Vandenbroucke-Grauls, C. W. Ang. Wilhelmina Kinderziekenhuis, UMCU, Utrecht: S. P. M. Geelen, T. F. W. Wolfs, L. J. Bont, N. Nauta. Coordinating Center: P. Reiss, D. O. Bezemer, A. I. van Sighem, C. Smit, F. W. N. M. Wit., T. S. Boender, S. Zaheri, M. Hillebregt, A. de Jong, D. Bergsma, P. Hoekstra, A. de Lang, S. Grivell, A. Jansen, M. J. Rademaker, M. Raethke, R. Meijering, S. Schnörr, L. de Groot, M. van den Akker, Y. Bakker, E. Claessen, A. El Berkaoui, J. Koops, E. Kruijne, C. Lodewijk, L. Munjishvili, B. Peeck, C. Ree, R. Regtop, Y. Ruijs, T. Rutkens, L. van de Sande, M. Schoorl, A. Timmerman, E. Tuijn, L. Veenenberg, S. van der Vliet, A. Wisse, T. Woudstra, B. Tuk.

Aquitaine Cohort (France)

Composition du Conseil scientifique:

Coordination: F. Bonnet, F. Dabis

Scientific committee: M. Dupon, V. Gaborieau, D. Lacoste, D. Malvy, P. Mercié, P. Morlat, D. Neau, JL. Pellegrin, S. Tchamgoué, E. Lazaro, C. Cazanave, M. Vandenhende, M. O. Vareil, Y. Gérard, P. Blanco, S. Bouchet, D. Breilh, H. Fleury, I. Pellegrin, G. Chêne, R. Thiébaut, L. Wittkop, L. Wittkop, O. Leleux, S. Lawson-Ayayi, A. Gimbert, S. Desjardin, L. Lacaze-Buzy, V. Petrov-Sanchez

Epidemiology and Methodology: F. Bonnet, G. Chêne, F. Dabis, R. Thiébaut, L. Wittkop

Infectious Diseases and Internal Medicine: K. André, N. Bernard, F. Bonnet, O. Caubet, L. Caunegre, C. Cazanave, I. Chossat, C. Courtault, FA. Dauchy, S. De Witte, D. Dondia, M. Dupon, P. Duffau, H. Dutronc, S. Farbos, I. Faure, H. Ferrand, V. Gaborieau, Y. Gerard, C. Greib, M. Hessamfar, Y. Imbert, D. Lacoste, P. Lataste, E. Lazaro, D. Malvy, J. Marie, M. Mechain, P. Mercié, E. Monlun, P. Morlat, D. Neau, A. Ochoa, JL. Pellegrin, T. Pistone, I. Raymond, M. C. Receveur, P. Rispal, L. Sorin, S. Tchamgoué, C. Valette, M. A. Vandenhende, M. O. Vareil, J. F. Viallard, H. Wille, G. Wirth.

Immunology: I. Pellegrin, P. Blanco

Virology: H. Fleury, Me. Lafon, P. Trimoulet, P. Bellecave, C. Tumiotto

Pharmacology: S. Bouchet, D. Breilh, F. Haramburu, G. Miremeont-Salamé

Data Collection, Project Management, and Statistical Analyses: MJ. Blaizeau, M. Decoin, C. Hannapier, E. Lenaud et A. Pougetoux; S. Delveaux, C. D’Ivernois, F. Diarra, B. Uwamaliya-Nziyumvira, O. Leleux; F. Le Marec, E. Boerg, S. Lawson-Ayayi;

IT department and eCRF development: G. Palmer, V. Conte, V. Sapparrart

AHOD (Australian HIV Observational Database, Australia):

Central coordination: M. Law*, K. Petoumenos, R. Puhr, R. Huang (Sydney, New South Wales). Participating physicians (city, state): R. Moore, S. Edwards, J. Hoy, K. Watson, N. Roth, H. Lau (Melbourne, Victoria); M. Bloch, D. Baker, A. Carr, D. Cooper (Sydney, New South Wales); M. O'Sullivan (Gold Coast, Queensland), D. Nolan, G. Guelfi (Perth, Western Australia).

BASS (Spain):

Central coordination: G. Calvo, F. Torres, S. Mateu (Barcelona);

Participating physicians (city): P. Domingo, M. A. Sambeat, J. Gatell, E. Del Cacho, J. Cadafalch, M. Fuster (Barcelona); C. Codina, G. Sirera, A. Vaqué (Badalona).

The Brussels St Pierre Cohort (Belgium):

Coordination: S. De Wit*, N. Clumeck, M. Delforge, C. Necsoi.

Participating physicians: N. Clumeck, S. De Wit*, A. F. Gennotte, M. Gerard, K. Kabeya, D. Konopnicki, A. Libois, C. Martin, M. C. Payen, P. Semaille, Y. Van Laethem.

The Brussels St Pierre Cohort (Belgium):

Coordination: S. De Wit*, N. Clumeck, M. Delforge, C. Necsoi.

Participating physicians: N. Clumeck, S. De Wit*, AF Gennotte, M. Gerard, K. Kabeya, D. Konopnicki, A. Libois, C. Martin, M. C. Payen, P. Semaille, Y. Van Laethem.

CPCRA (USA):

Central coordination: J. Neaton, G. Bartsch, W. M. El-Sadr*, E. Krum, G. Thompson, D. Wentworth;

Participating physicians (city, state): 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 (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); L. R. Crane (Detroit, Michigan); J. Sampson (Portland, Oregon); J. Baxter (Camden, New Jersey).

EuroSIDA (multinational)

Steering Committee: J. Gatell, B. Gazzard, A. Horban, I. Karpov, M. Losso, A. d’Arminio Monforte, C. Pedersen, M. Ristola, A. Phillips, P. Reiss, J. Lundgren, J. Rockstroh

Chair: J. Rockstroh

Study Co-leads: A. Mocroft, O. Kirk

Coordinating Centre Staff: O. Kirk, L. Peters, C. Matthews, A. H. Fischer, A. Bojesen, D. Raben, D. Kristensen, K. Grønborg Laut, J. F. Larsen, D. Podlekareva

Statistical Staff: A. Mocroft, A. Phillips, A. Cozzi-Lepri, L. Shepherd, A. Schultze, S. Amele

The multicenter study group, EuroSIDA (national coordinators in parenthesis).

Argentina: (M. Losso), M. Kundro, Hospital JM Ramos Mejia, Buenos Aires.

Austria: (B. Schmied), Pulmologisches Zentrum der Stadt Wien, Vienna; R. Zangerle, Medical University Innsbruck, Innsbruck.

Belarus: (I. Karpov), A. Vassilenko, Belarus State Medical University, Minsk; V. M. Mitsura, Gomel State Medical University, Gomel; D. Paduto, Regional AIDS Centre, Svetlogorsk.

Belgium: (N. Clumeck), S. De Wit, M. Delforge, Saint-Pierre Hospital, Brussels; E. Florence, Institute of Tropical Medicine, Antwerp; L. Vandekerckhove, University Ziekenhuis Gent, Gent.

Bosnia-Herzegovina: (V. Hadziosmanovic), Klinicki Centar Univerziteta Sarajevo, Sarajevo.

Croatia: (J. Begovac), University Hospital of Infectious Diseases, Zagreb.

Czech Republic: (L. Machala), D. Jilich, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen.

Denmark: G. Kronborg, T. Benfield, Hvidovre Hospital, Copenhagen; J. Gerstoft, T Katzenstein, Rigshospitalet, Copenhagen; N. F. Møller, C. Pedersen, Odense University Hospital, Odense; L. Ostergaard, Skejby Hospital, Aarhus; L. Wiese, Roskilde Hospital, Roskilde; L. N. Nielsen, Hillerod Hospital, Hillerod.

Estonia: (K. Zilmer), West-Tallinn Central Hospital, Tallinn; J. Smidt, Nakkusosakond Siseklinik, Kohtla-Järve.

Finland: (M. Ristola), I. Aho, Helsinki University Central Hospital, Helsinki.

France: (J.-P. Viard), Hôtel-Dieu, Paris; P.-M. Girard, Hospital Saint-Antoine, Paris; C. Pradier, E. Fontas, Hôpital de l'Archet, Nice; C. Duvivier, Hôpital Necker-Enfants Malades, Paris.

Germany: (J. Rockstroh), Universitäts Klinik Bonn; R Schmidt, Medizinische Hochschule Hannover; O. Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; H. J. Stellbrink, IPM Study Center, Hamburg; C. Stefan, J. W. Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne.

Georgia: (N. Chkhartishvili) Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi

Greece: (P. Gargalianos), G. Xylomenos, K. Armenis, Athens General Hospital “G Gennimatas”; H. Sambatakou, Ippokration General Hospital, Athens.

Hungary: (J. Szlávik), Szent Lásló Hospital, Budapest.

Iceland: (M. Gottfredsson), Landspitali University Hospital, Reykjavik.

Ireland: (F. Mulcahy), St. James's Hospital, Dublin.

Israel: (I. Yust), D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; E. Shahar, G. Hassoun, Rambam Medical Center, Haifa; H. Elinav, M. Haouzi, Hadassah University Hospital, Jerusalem; D. Elbirt, Z. M. Sthoeger, AIDS Center (Neve Or), Jerusalem.

Italy: (A. D’Arminio Monforte), Istituto Di Clinica Malattie Infettive e Tropicale, Milan; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; F. Mazzotta, A. Gabbuti, Ospedale S Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; M. Zaccarelli, A. Antinori, R. Acinapura, M. Plazzi, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, A. Castagna, N. Gianotti, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan.

Latvia: (B. Rozentale), Infectology Centre of Latvia, Riga.

Lithuania: (V. Uzdaviniene) Vilnius University Hospital Santariskiu Klinikos, Vilnius; R. Matulionyte, Center of Infectious Diseases, Vilnius University Hospital Santariskiu Klinikos, Vilnius.

Luxembourg: (T. Staub), R. Hemmer, Centre Hospitalier, Luxembourg.

Netherlands: (P. Reiss), Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam.

Norway: (V. Ormaasen), A. Maeland, J. Bruun, Ullevål Hospital, Oslo.

Poland: (B. Knysz), J. Gasiorowski, M. Inglot, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; R. Flisiak, A. Grzeszczuk, Medical University, Bialystok; M. Parczewski, K. Maciejewska, B. Aksak-Was, Medical University, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; T. Smiatacz, M. Gensing, Medical University, Gdansk; E. Jablonowska, E. Malolepsza, K. Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz; I. Mozer-Lisewska, Poznan University of Medical Sciences, Poznan.

Portugal: (L. Caldeira), Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon.

Romania: (R. Radoi), C. Oprea, Spitalul de Boli Infectioase si Tropicale: Dr. Victor Babes, Bucarest.

Russia: (A. Panteleev), O. Panteleev, St Petersburg AIDS Centre, St Peterburg; A. Yakovlev, Medical Academy Botkin Hospital, St Petersburg; T. Trofimora, Novgorod Centre for AIDS, Novgorod; I. Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E. Kuzovatova, Nizhny Novgorod Scientific and Research Institute of Epidemiology and Microbiology named after Academician I. N. Blokhina, Nizhny Novogrod; E. Borodulina, E. Vdoushkina, Samara State Medical University, Samara.

Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade.

Slovenia: (J. Tomazic), University Clinical Centre Ljubljana, Ljubljana.

Spain: (J. M. Gatell), J. M. Miró, Hospital Clinic Universitari de Barcelona, Barcelona; S. Moreno, J. M. Rodriguez, Hospital Ramon y Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, Hospital Germans Trias i Pujol, Badalona; P. Domingo, M. Gutierrez, G. Mateo, M. A. Sambeat, Hospital Sant Pau, Barcelona; J. M. Laporte, Hospital Universitario de Alava, Vitoria-Gasteiz.

Sweden: (C. Carlander), A. Sonnerborg, Karolinska University Hospital, Stockholm; I. Brännström, Venhälsan-Sodersjukhuset, Stockholm; L. Flamholc, Malmö University Hospital, Malmö.

Switzerland: (A. Scherrer), R. Weber, University Hospital Zurich; M. Cavassini, University Hospital Lausanne; A. Calmy, University Hospital Geneva; H. Furrer, University Hospital Bern; M. Battegay, University Hospital Basel; P. Schmid, Cantonal Hospital St. Gallen.

Ukraine: A. Kuznetsova, Kharkov State Medical University, Kharkov; G. Kyselyova, Crimean Republican AIDS Centre, Simferopol; M. Sluzhynska, Lviv Regional HIV/AIDS Prevention and Control CTR, Lviv.

United Kingdom: (B. Gazzard), St. Stephen's Clinic, Chelsea and Westminster Hospital, London; A. M. Johnson, E. Simons, S. Edwards, Mortimer Market Centre, London; A. Phillips, M. A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); C. Orkin, Royal London Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St. Mary's, London; A. Clarke, Royal Sussex County Hospital, Brighton; C. Leen, Western General Hospital, Edinburgh.

The following centers have previously contributed data to EuroSIDA:

Infectious Diseases Hospital, Sofia, Bulgaria; Hôpital de la Croix Rousse, Lyon, France; Hôpital de la Pitié-Salpétière, Paris, France; Unité INSERM, Bordeaux, France; Hôpital Edouard Herriot, Lyon, France; Bernhard Nocht Institut für Tropenmedizin, Hamburg, Germany; 1st I.K.A Hospital of Athens, Athens, Greece; Ospedale Riuniti, Divisione Malattie Infettive, Bergamo, Italy; Ospedale di Bolzano, Divisione Malattie Infettive, Bolzano, Italy; Ospedale Cotugno, III Divisione Malattie Infettive, Napoli, Italy; Dérer Hospital, Bratislava, Slovakia; Hospital Carlos III, Departamento de Enfermedades Infecciosas, Madrid, Spain; Kiev Centre for AIDS, Kiev, Ukraine; Luhansk State Medical University, Luhansk, Ukraine; Odessa Region AIDS Center, Odessa, Ukraine

HIV-BIVUS (Sweden):

Central coordination: L. Morfeldt, G. Thulin, A. Sundström.

Participating physicians (city): B. Åkerlund (Huddinge); K. Koppel, A. Karlsson (Stockholm); L. Flamholc, C. Håkangård (Malmö).

The ICONA Foundation (Italy):

Board of Directors

A. d’Arminio Monforte (President), A. Antinori, A. Castagna, F. Castelli, R. Cauda, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, G. C. Marchetti, C. F. Perno, F. von Schloesser, P. Viale

Scientific Secretary

A. d’Arminio Monforte, A. Antinori, A. Castagna, F. Ceccherini-Silberstein, A. Cozzi-Lepri, E. Girardi, S. Lo Caputo, C. Mussini, M. Puoti

Steering Committee

M. Andreoni, A. Ammassari, A. Antinori, C. Balotta, A. Bandera, P. Bonfanti, S. Bonora, M. Borderi, A. Calcagno, L. Calza, M. R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, A. Cingolani, P. Cinque, A. Cozzi-Lepri, A. d’Arminio Monforte, A. De Luca, A. Di Biagio, E. Girardi, N. Gianotti, A. Gori, G. Guaraldi, G. Lapadula, M. Lichtner, S. Lo Caputo, G. Madeddu, F. Maggiolo, G. Marchetti, S. Marcotullio, L. Monno, C. Mussini, S. Nozza, M. Puoti, E. Quiros Roldan, R. Rossotti, S. Rusconi, M. M. Santoro, A. Saracino, M. Zaccarelli.

Statistical and Monitoring Team

A. Cozzi-Lepri, I. Fanti, L. Galli, P. Lorenzini, A. Rodano, M. Shanyinde, A. Tavelli

Biological Bank INMI

F. Carletti, S. Carrara, A. Di Caro, S. Graziano, F. Petrone, G. Prota, S. Quartu, S. Truffa

Participating Physicians and Centers

Italy: A. Giacometti, A. Costantini, V. Barocci (Ancona); G. Angarano, L. Monno, C. Santoro (Bari); F. Maggiolo, C. Suardi (Bergamo); P. Viale, V. Donati, G. Verucchi (Bologna); F. Castelli, C. Minardi, E. Quiros Roldan (Brescia); T. Quirino, C. Abeli (Busto Arsizio); P. E. Manconi, P. Piano (Cagliari); B. Cacopardo, B. Celesia (Catania); J. Vecchiet, K. Falasca (Chieti); A. Pan, S. Lorenzotti (Cremona); L. Sighinolfi, D. Segala (Ferrara); F. Mazzotta, F. Vichi (Firenze); G. Cassola, C. Viscoli, A. Alessandrini, N. Bobbio, G. Mazzarello (Genova); C. Mastroianni, V. Belvisi (Latina); P. Bonfanti, I. Caramma (Lecco); A. Chiodera, P. Milini (Macerata); A. d’Arminio Monforte, M. Galli, A. Lazzarin, G. Rizzardini, M. Puoti, A. Castagna, G. Marchetti, M. C. Moioli, R. Piolini, A. L. Ridolfo, S. Salpietro, C. Tincati (Milano); C. Mussini, C. Puzzolante (Modena); A. Gori, G. Lapadula (Monza); N. Abrescia, A. Chirianni, G. Borgia, R. Orlando, G. Bonadies, F. Di Martino, I. Gentile, L. Maddaloni (Napoli); A. M. Cattelan, S. Marinello (Padova); A. Cascio, C. Colomba (Palermo); F. Baldelli, E. Schiaroli (Perugia); G. Parruti, F. Sozio (Pescara); G. Magnani, M. A. Ursitti (Reggio Emilia); M. Andreoni, A. Antinori, R. Cauda, A. Cristaudo, V. Vullo, R. Acinapura, G. Baldin, M. Capozzi, S. Cicalini, A. Cingolani, L. Fontanelli Sulekova, G. Iaiani, A. Latini, I. Mastrorosa, M. M. Plazzi, S. Savinelli, A. Vergori (Roma); M. Cecchetto, F. Viviani (Rovigo); G. Madeddu, P. Bagella (Sassari); A. De Luca, B. Rossetti (Siena); A. Franco, R. Fontana Del Vecchio (Siracusa); D. Francisci, C. Di Giuli (Terni); P. Caramello, G. Di Perri, S. Bonora, G. C. Orofino, M. Sciandra (Torino); M. Bassetti, A. Londero (Udine); G. Pellizzer, V. Manfrin (Vicenza) G. Starnini, A. Ialungo (Viterbo).

Nice HIV Cohort (France):

Central coordination: C. Pradier*, E. Fontas, K. Dollet, C. Caissotti.

Participating physicians: P. Dellamonica, E. Bernard, J. Courjon, E. Cua, F. De Salvador-Guillouet, J. Durant, C. Etienne, S. Ferrando, V. Mondain-Miton, A. Naqvi, I. Perbost, S. Pillet, B. Prouvost-Keller, P. Pugliese, V. Rio, K. Risso, P. M. Roger.

SHCS (Swiss HIV Cohort Study, Switzerland):

The data are gathered by the 5 Swiss university hospitals, 2 Cantonal hospitals, 15 affiliated hospitals, and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers).

Members of the Swiss HIV Cohort Study:

V. Aubert, M. Battegay, E. Bernasconi, J. Böni, D. L. Braun, H. C. Bucher, A. Calmy, M. Cavassini, A. Ciuffi, G. Dollenmaier, M. Egger, L. Elzi, J. Fehr, J. Fellay, H. Furrer (Chairman of the Clinical and Laboratory Committee), C. A. Fux, H. F. Günthard (President of the SHCS), D. Haerry (Deputy of the “Positive Council”), B. Hasse, H. H. Hirsch, M. Hoffmann, I. Hösli, C. Kahlert, L. Kaiser, O. Keiser, T. Klimkait, R. D. Kouyos, H. Kovari, B. Ledergerber, G. Martinetti, B. Martinez de Tejada, C. Marzolini, K. J. Metzner, N. Müller, D. Nicca, G. Pantaleo, P. Paioni, A. Rauch (Chairman of the Scientific Board), C. Rudin (Chairman of the Mother & Child Substudy), A. U. Scherrer (Head of Data Center), P. Schmid, R. Speck, M. Stöckle, P. Tarr, A. Trkola, P. Vernazza, G. Wandeler, R. Weber*, S. Yerly.

RESPOND

AIDS Therapy Evaluation in the Netherlands Cohort (ATHENA): F. Wit, M. vd Valk, M. Hillebregt, Stichting HIV Monitoring (SHM), Amsterdam, Netherlands

Australian HIV Observational Database (AHOD): K. Petoumenos, M. Law, J. Hutchinson, D. Rupasinghe, W. Min Han, UNSW Sydney, Sydney, Australia

Austrian HIV Cohort Study (AHIVCOS): R. Zangerle, H. Appoyer, Medizinische Universität Innsbruck, Innsbruck, Austria

Brighton HIV cohort: J. Vera, A. Clarke, B. Broster, L. Barbour, D. Carney, L. Greenland, R. Coughlan, Lawson Unit, Royal Sussex County Hospital, University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom

CHU Saint-Pierre, S. De Wit, M Delforge, Centre de Recherche en Maladies Infectieuses a.s.b.l., Brussels, Belgium

Croatian HIV cohort: J. Begovac, University Hospital of Infectious Diseases, Zagreb, Croatia

EuroSIDA Cohort: G. Wandeler, CHIP, Rigshospitalet, Region H, Copenhagen, Denmark

Frankfurt HIV Cohort Study: C. Stephan, M. Bucht, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany

Georgian National AIDS Health Information System (AIDS HIS): N. Chkhartishvili, O. Chokoshvili, Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia

Italian Cohort Naive Antiretrovirals (ICONA): A. d’Arminio Monforte, A. Rodano, A. Tavelli, I. Fanti, Icona Foundation, Milan, Italy

Modena HIV Cohort: C. Mussini, V. Borghi, Università degli Studi di Modena, Modena, Italy

Nice HIV Cohort: C. Pradier, E. Fontas, K. Dollet, C. Caissotti, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Department of Public Health, UR2CA, Nice, France

PISCIS Cohort Study: J. Casabona, J. M. Miro, Centre Estudis Epidemiologics de ITS i VIH de Catalunya (CEEISCAT), Badalona, Spain

Royal Free Hospital Cohort: C. Smith, F. Lampe, M. Johnson, F. Burns, C. Chaloner, Royal Free Hospital, University College London, London, United Kingdom

San Raffaele Scientific Institute (CSL HIV Cohort): A. Castagna, V. Spagnuolo, C. Muccini, S. Nozza, R. Lolatto, Milan, Italy

Swedish InfCare HIV Cohort: A. Sönnerborg, C. Carlander, P. Nowak, J. Vesterbacka, L. Mattsson, D. Carrick, K. Stigsäter, Department of Infectious Diseases, Karolinska University Hospital, and Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Sweden

Swiss HIV Cohort Study (SHCS): H. Günthard, K. Kusejko, B. Ledergerber, H. Bucher, University of Zurich, Zurich, Switzerland

University Hospital Bonn: J. C. Wasmuth, J Rockstroh, Bonn, Germany

University Hospital Cologne: J. J. Vehreschild, G. Fätkenheuer, N. Schulze, B. Franke, Cologne, Germany

RESPOND Executive Committee

L. Ryom*, M. Law*, J. Rooney, I. McNicholl, V. Vannappagari, H. Garges, K. Petoumenos, G. Wandeler, R. Zangerle, C. Smith, S. De Wit, J. Lundgren, H. Günthard, L .Young, R. Campo

*Chairs

RESPOND Scientific Steering Committee

J. Lundgren*, H. Günthard*, J. Kowalska, D. Raben, L. Ryom, J. Rockstroh, L. Peters, O. Kirk, D. Podlekareva, A. Volny-Anne, N. Dedes, E. D. Williams, N. Chkhartishvili, R. Zangerle, K. Petoumenos, F. Wit, C. Necsoi, G. Wandeler, C. Stephan, C. Pradier, A. D’Arminio Monforte, C. Mussini, A. Bruguera, H. Bucher, A. Sönnerborg, J. J. Vehreschild, J. C. Wasmuth, C. Smith, A. Castagna, J. Vera, J. Rooney, I. McNicholl, V. Vannappagari, H. Garges, J. Begovac, L. Young, R. Campo

*Chairs

Community Representatives:

Alain Volny-Anne, Nikos Dedes, Luis Mendão (European AIDS Treatment Group), Esther Dixon Williams (UK)

RESPOND Staff

Coordinating Centre Staff: J. F. Larsen, L. Peters, N. Jaschinski, A. Timiryasova, B. Neesgaard, O. Fursa, L. Ryom, M. L. Jakobsen, C. Kraef, M. Gardizi

Data Management Staff: D. Raben, K. Andersen, L. Ramesh Kumar, T. W. Elsing, S. Shahi, O. Valdenmaiier

Statistical Staff: J. Reekie, L. Greenberg, L. Bansi-Matharu, A. Pelchen-Matthews, K. Petoumenos, D. Byonanebye, E. Tusch, W. Bannister, A. Roen

Financial support. The D:A:D study was supported by the Highly Active Antiretroviral Therapy Oversight Committee, a collaborative committee with representation from academic institutions, the European Agency for the Evaluation of Medicinal Products, the US Food and Drug Administration, the patient community, and pharmaceutical companies with licensed anti-human immunodeficiency virus (HIV) drugs in the European Union: Abbvie, Bristol-Myers Squibb, Gilead Sciences Inc, ViiV Healthcare, Merck & Co. Inc, and Janssen Pharmaceuticals. The study was also supported by a grant ( DNRF126) from the Danish National Research Foundation (CHIP & PERSIMUNE); a grant from the Dutch Ministry of Health, Welfare and Sport through the Center for Infectious Disease Control of the National Institute for Public Health and the Environment to Stiching HIV Monitoring (ATHENA); and a grant from the Agence nationale de recherches sur le sida et les hépatites virales (ANRS, Action Coordonnée no.7, Cohortes) to the Aquitaine Cohort. The Australian HIV Observational Database (AHOD) is funded as part of the Asia Pacific HIV Observational Database, a program of The Foundation for AIDS Research, amfAR, and is supported in part by a grant from the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID; grant U01-AI069907) and by unconditional grants from Merck Sharp & Dohme, Gilead Sciences, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen-Cilag, and ViiV Healthcare. The Kirby Institute is funded by the Department of Health and Ageing Australian Government and is affiliated with the Faculty of Medicine, the University of New South Wales; by grants from the Fondo de Investigación Sanitaria (grant FIS 99/0887) and Fundación para la Investigación y la Prevención del SIDA en Espanã (grant FIPSE 3171/00), to the Barcelona Antiretroviral Surveillance Study (BASS); by the NIAID, NIH (grants 5U01AI042170-10, 5U01AI046362-03), to the Terry Beirn Community Programs for Clinical Research on AIDS; by primary funding provided by the European Union's Seventh Framework Programme for research, technological development and demonstration under EuroCoord (grant260694), and unrestricted grants by Bristol-Myers Squibb, Janssen R&D, Merck and Co, Inc, Pfizer Inc, GSK LLC (the participation of centers from Switzerland is supported by the Swiss National Science Foundation (grant108787) to the EuroSIDA study; by unrestricted educational grants of AbbVie, Bristol-Myers Squibb, Gilead Sciences, GSK, Pfizer, and Janssen Pharmaceuticals to the Italian Cohort Naive to Antiretrovirals (the ICONA Foundation); and financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant 148522) and by the SHCS Research Foundation.

The International Cohort Consortium of Infectious Disease (RESPOND) is supported by the CHU St Pierre Brussels HIV Cohort, Austrian HIV Cohort Study, Australian HIV Observational Database, AIDS Therapy Evaluation in the Netherlands National Observational HIV Cohort, EuroSIDA Cohort, Frankfurt HIV Cohort Study, Georgian National AIDS Health Information System, Nice HIV Cohort, ICONA Foundation, Modena HIV Cohort, PISCIS Cohort Study, Swiss HIV Cohort Study, Swedish InfCare HIV Cohort, Royal Free HIV Cohort Study, San Raffaele Scientific Institute, University Hospital Bonn HIV Cohort, University of Cologne HIV Cohort, Brighton HIV Cohort, and National Croatian HIV Cohort. RESPOND is further financially supported by ViiV Healthcare, Merck Life Sciences, Gilead Sciences, and the AHOD Cohort (grant U01-AI069907 from the NIH, and the National Health and Medical Research Council, Australia (grant GNT1050874).

Data sharing. The RESPOND Scientific Steering Committee (SSC) encourages the submission of concepts for research projects. Online research concepts (please see https://chip.dk/Research/Studies/RESPOND/Study%C2%ADdocuments) should be submitted to the RESPOND secretariat ([email protected]). The secretariat will direct the proposal to the relevant scientific interest group, where the proposal will initially be discussed for scientific relevance before being submitted to the SSC for review. All data within RESPOND from individual cohorts are de­identified. The present RESPOND data structure and a list of all collected variables and their definitions can be found in the latest version of Standard Operating Procedure for data transfer in RESPOND, EuroSIDA, MISTRAL, and CARE, which is publicly available at https://chip.dk/Research/Studies/RESPOND/Study%C2%ADdocuments. For any inquiries regarding data sharing, please contact the RESPOND secretariat ([email protected]) and Dorthe Raben, Director of Research Coordination ([email protected]).

Author notes

Team members of the cohort studies are listed in the acknowledgments.

Potential conflicts of interest. A. M. reports consulting fees from Eiland and Bonnin. H. F. G. reports honoraria for data and safety monitoring board or advisory board membership from Merck, Gilead Sciences, ViiV Healthcare, GSK, Janssen, Johnson & Johnson, and Novartis; a travel grant from Gilead Sciences; unrestricted research grants from Gilead Sciences; grants or contracts paid to institution from the Swiss National Science Foundation, Swiss HIV Cohort Study, National Institute of Health; and an unrestricted research grant from Gilead Sciences, Yvonne Jacob Foundation. J. J. V. reports personal fees from Merck Sharp & Dohme, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), University Hospital Freiburg/ Congress and Communication, Academy for Infectious Medicine, University Manchester, German Society for Infectious Diseases (DGI), Ärztekammer Nordrhein, University Hospital Aachen, Back Bay Strategies, German Society for Internal Medicine (DGIM), Shionogi, Molecular Health, Netzwerk Universitätsmedizin, Janssen, NordForsk, Biontech, and APOGEPHA and grants from Merck Sharp & Dohme, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), German Federal Ministry of Education and Research (BMBF), Deutsches Zetrum für Luft- und Raumfahrt (DLR), University of Bristol, Rigshospitalet Copenhagen, and Network University Medicine. F. W. reports personal fees for attending advisory boards from ViiV Healthcare. A. d’A. M. reports fees for lectures sponsored by ViiV, Gilead, and Pfizer and projects sponsored (to institution) by ViiV, Gilead, and Merck Sharpe & Dohme. V. S. reports CME education fees from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare. C. C. reports an unrestricted Nordic Fellowship Grant from Gilead Sciences Nordic; honoraria from GSK and ViiV, Gilead Sciences, and Merck Sharp & Dohme (paid to institution), and has participated on an advisory board for GSK, ViiV and Gilead Sciences (paid to institution). P. S. reports honoraria and/or speaking fees from Gilead, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, and ViiV Healthcare and a research grant from ViiV Healthcare, all outside of the submitted work. A. C. reports consulting fees from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare; honoraria for presentations from Gilead Sciences and ViiV Healthcare; support for travel to advisory board and to study investigator meetings from Merck Sharp & Dohme; and receipt of study medication and supplies from Merck Sharp & Dohme. K. P. reports unrestricted research funding made to institution by Gilead Australia and ViiV Healthcare Australia. F. Bonnet reports grants from Gilead and ViiV Healthcare and honoraria from Gilead, ViiV Healthcare, and Merck Sharp & Dohme. S. D. W. reports payments from the D:A:D and RESPOND studies paid to institution. J. G. is an employee of Gilead Sciences. V. V. is an employee of ViiV Healthcare. L. Y. is an employee of Merck Sharp & Dohme. C. S. reports honoraria for preparation of educational materials from Gilead Sciences and honoraria for speaking and preparation of educational materials from ViiV Healthcare. All remaining authors: No reported conflicts of interest.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.