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Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting

Greenberg, Lauren MSca; Ryom, Lene MD, PhDb; Wandeler, Gilles MDc; Grabmeier-Pfistershammer, Katharina MDd; Öllinger, Angela MDd; Neesgaard, Bastian MDb; Stephan, Christoph MDe; Calmy, Alexandra MDf; Rauch, Andri MDc; Castagna, Antonella MDg; Spagnuolo, Vincenzo MDg; Johnson, Margaret MD, DMsCh; Stingone, Christof MDh; Mussini, Cristina MDi; De Wit, Stéphane MDj; Necsoi, Coca MDj; Campins, Antoni A. MDk; Pradier, Christian MDl; Stecher, Melanie MScm; Wasmuth, Jan-Christian MDn; Monforte, Antonella d'Arminio MDo; Law, Matthew PhDp; Puhr, Rainer PhDp; Chkhartishvilli, Nikoloz MD, PhDq; Tsertsvadze, Tengiz MD, PhDq; Garges, Harmony MDr; Thorpe, David PhDs; Lundgren, Jens D. MD, DMsCb; Peters, Lars MDb; Bansi-Matharu, Loveleen PhDa; Mocroft, Amanda PhDa; RESPOND Study Group

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1, 2020 - Volume 83 - Issue 3 - p 240-250
doi: 10.1097/QAI.0000000000002250

Abstract

INTRODUCTION

Integrase strand transfer inhibitors (INSTIs) are one of the latest antiretroviral drug classes to be approved for use as part of combination antiretroviral therapy (ART) regimens to control HIV.1 Current HIV treatment guidelines recommend that initial ART regimens for adults include a backbone of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a third agent consisting of an INSTI, boosted protease inhibitor (PI/b) or NNRTI.2,3 There are currently 4 INSTIs approved by the European Medicines Agency. Raltegravir (RAL)4,5 was the first to be approved in 2008, followed by elvitegravir (EVG)6,7 in 2013, dolutegravir (DTG)8–11 in 2014, and bictegravir (BIC)12,13 in 2018.

Commonly reported adverse effects (AEs) associated with INSTIs include headache, nausea, and sleep disturbances.14 In addition, cobicistat-boosted EVG (EVG/c) and DTG may cause inhibition of renal tubular secretion of creatinine, causing an artefactual increase in creatinine plasma levels not reflective of a declining renal function.10,15,16 Although the frequency of drug–drug interactions on INSTIs as a class is relatively low, it is higher on EVG, because of the need for a pharmacokinetic enhancer.2

Several randomized controlled trials (RCTs) have demonstrated good virological efficacy, fewer AEs, and lower rates of discontinuation with INSTIs compared with NNRTI,6,10,17–20 and PI/b.7,15,21–24 These results have been confirmed in small observational studies.14,25,26 However, despite the growing evidence, limited data exist on the choice of INSTIs and discontinuation of INSTIs in larger and more heterogeneous real-world settings. Access to individual INSTIs and reasons for discontinuation of INSTIs may differ among countries and subgroups, such as men vs women. In addition, because of their presumed favorable safety profile, it is likely that a higher proportion of those with existing comorbidities are receiving INSTIs.

We aimed to describe the characteristics of those initiating INSTIs for the first time in heterogeneous real-world settings across Europe and Australia. We also aimed to describe time to and reasons for discontinuation of initial INSTI regimens and describe the characteristics of those discontinuing INSTIs.

METHODS

Study Design and Participants

The International Cohort Consortium of Infectious Diseases (RESPOND) is a collaboration of 14 observational cohort studies across Europe and Australia, including 26,415 individuals living with HIV-1. Demographic and clinical data were retrospectively collected back to 2012 and are prospectively collected from 2017.

Standardized data including information on demographics, HIV-related factors, ART start and stop dates, and reason for discontinuation, coinfections, comorbidities, and biomarkers are collected at time of enrolment and annually thereafter as part of routine clinical care (details at https://www.chip.dk/Studies/RESPOND). All cohorts used the HIV Cohorts Data Exchange Protocol (HICDEP) for data collection (details at https://hicdep.org/).

Individuals were included in this analysis if they had started DTG, EVG/c, or RAL (persons were not necessarily ART-naive) after the latest of local cohort enrolment and January 1, 2012, were aged ≥16, and had a CD4 cell count and viral load (VL) measurement before or within 6 months after starting an INSTI. Individuals were excluded from the analysis if they had missing information on gender. Final follow-up in our study was the last clinic visit before 2018.

Definition of Outcomes

The first outcome was defined as uptake of DTG, EVG/c, or RAL. Individuals starting more than one INSTI during follow-up were included in the first INSTI group they were exposed to.

The second outcome was defined as discontinuation of first INSTI regimen during follow-up, provided individuals had been on the INSTI for at least 7 days (<1% of discontinuations occurred within 7 days of starting INSTIs). Discontinuation was not counted if an individual switched from a single-tablet regimen (STR) to its individual components or vice versa, while remaining on the same INSTI, provided there was no interruption between treatments, nor if the backbone changed, provided the INSTI component remained the same. Discontinuations were split into discontinuation within 6 months and after 6 months of INSTI initiation.

Definition of Potential Predictors

The following variables, defined before or at INSTI initiation, were considered as potential predictors: year of starting INSTI, age, gender, HIV risk category, ethnicity, CD4 cell count nadir, CD4 cell count at INSTI initiation, smoking status, ART experience and viral suppression status, viral hepatitis B and C status (HBV/HCV), hypertension, diabetes, AIDS-defining event, non–AIDS-defining malignancy, end stage liver disease, cardiovascular disease (CVD), fracture, chronic kidney disease, and geographical region. For the INSTI discontinuation models, INSTI type was fitted as a potential predictor.

CD4 cell count at INSTI initiation was taken as the most recent CD4 count before initiation. If no CD4 count was measured, the first measurement within 6 months after INSTI start was used for both CD4 at INSTI initiation and CD4 cell nadir.

Geographical region was categorized as in previous EuroSIDA analyses.27 Because of low numbers, Australia was combined with Northern Europe in the analysis models, and Eastern Central Europe was combined with Eastern Europe.

Statistical Methods

Risk ratios using multinomial logistic regression were used to assess associations between baseline characteristics and the likelihood of starting RAL compared with DTG and of starting EVG/c compared with DTG. Baseline was defined as date of INSTI start. DTG was chosen as the reference category, because it was the largest group and most recently approved INSTI. Each variable was included in univariable models and then all variables were fitted simultaneously in a multivariable model.

Results of the multivariable model were compared between ART-naive, ART-experienced with VL <400 copies/mL, and ART-experienced with VL ≥400 copies/mL. Prespecified subgroup analyses were performed by fitting an interaction term between age and each of gender, HBV/HCV status, and each comorbidity listed above.

Discontinuation of DTG, EVG/c, and RAL was summarized using Kaplan–Meier (KM) estimates. Reasons for discontinuation of each INSTI were summarized. For each drug discontinuation, one underlying reason was provided by the participating cohort at the clinician's judgement. Reasons reported were grouped into treatment failure, toxicity, patient/physician choice (without further details), treatment simplification, other, and unknown. Discontinuations due to toxicity were further broken down into the individual reasons provided. Patient/physician choice was included as a marker of potential toxicity, as in previous EuroSIDA studies.28

Cox proportional hazards models were used to assess factors associated with time to discontinuation, including all variables listed above. Each variable was included in univariable models and then all were fitted simultaneously in a multivariable model. Individuals were censored at final follow-up, defined as last clinical visit, drop out date as defined by the cohort, or date of death.

Prespecified subgroup analyses were performed between INSTI type and each of gender, age, HIV risk group, HBV/HCV status, and each comorbidity listed above.

In all analysis models, an unknown category was used to account for missing data for categorical variables. Because some cohorts were missing data on specific comorbidities, we did not adjust for cohort in the primary analysis. Sensitivity analyses were performed including cohort as an explanatory variable and excluding comorbidities. In addition, the models were rerun using multiple imputation by chained equations to account for missing data with 10 imputations, including the same variables as those included in the primary analysis model. Results were combined using Rubin's rules.

Analyses were performed using Stata/SE 15.0. P-values are 2 sided and a P-value <0.05 was defined as statistically significant.

RESULTS

Overall, 10,366 participants in RESPOND started an INSTI and of these, 9702 (93.6%) were included in the analysis. Reasons for exclusion from the analysis are presented in Figure 1, Supplemental Digital Content 1, https://links.lww.com/QAI/B408. Of those included, 5051 (52.1%) started DTG, 1933 (19.9%) started EVG/c, and 2718 (28.0%) started RAL. Of those on DTG and EVG/c, 35.1% and 88.4% were on STRs, respectively. The most commonly used backbone for DTG was abacavir (ABC) and lamivudine (3 TC) (52.0%) and for EVG/c and RAL tenofovir disoproxil fumarate (TDF) with emtricitabine (FTC) (63.4% and 49.2%, respectively).

Baseline demographic and clinical characteristics are presented in Table 1. Most INSTI users were male, of white ethnicity and ART-experienced with a suppressed VL. The proportion who were ART-naive was highest on EVG/c (30.4% on EVG/c vs 20.5% on RAL, and 23.5% on DTG, P < 0.001). There was a high incidence of previous AIDS-defining events (21.0% on DTG, 28.3% on RAL, and 13.2% on EVG/c, P < 0.001) and comorbidities, including hypertension, diabetes, and previous CVD (proportion with at least one comorbidity: 37.6% on DTG, 33.1% on RAL, and 27.7% on EVG/c, P < 0.001).

TABLE 1.
TABLE 1.:
Baseline Characteristics of Persons Starting INSTIs in RESPOND, Overall and by INSTI Type—n (%) Unless Stated Otherwise
TABLE 1-A.
TABLE 1-A.:
Baseline Characteristics of Persons Starting INSTIs in RESPOND, Overall and by INSTI Type—n (%) Unless Stated Otherwise

Uptake of INSTIs

Results from the univariable and multivariable multinomial logistic regression models are presented in Table 2. After adjustment, the likelihood of starting RAL or EVG/c compared with DTG decreased over time. Participants in Eastern and Southern Europe were more likely to start RAL or EVG/c compared with those in Western Europe. Increasing age at INSTI initiation was associated with an increased likelihood of starting RAL, but a decreased likelihood of starting EVG/c. Female gender was also associated with a decreased likelihood of starting EVG/c. The likelihood of starting RAL was higher for participants who were ART-naive or ART-experienced with ongoing viremia compared with those who were ART-experienced with a suppressed VL. In general, participants with comorbidities were more likely to start RAL, but less likely to start EVG/c compared with DTG (Table 2). Adjusting additionally for the nucleoside backbone did not change our findings, except HBV coinfection, which was no longer associated with choice of INSTI.

TABLE 2.
TABLE 2.:
Associations Between Characteristics at INSTI Start and Choice of INSTIs—Multivariable Analysis

We found a significant interaction between age and gender (P-value for interaction <0.001) for RAL vs DTG, showing that females were more likely to start RAL compared with men in younger age groups, but were less likely to start RAL in older age groups (see Figure 2, Supplemental Digital Content 1, https://links.lww.com/QAI/B408). Other prespecified subgroup analyses were nonsignificant. Results were stratified by ART experience at baseline with similar findings. We repeated analyses adjusting for cohort instead of comorbidities with similar results. Multiple imputation to account for missing data also showed similar results (data not shown). As a post-hoc analysis, we repeated analyses only including those starting an INSTI from 2015 (when DTG, EVG/c and RAL were available) and found similar results.

Discontinuation of INSTIs

Median follow-up time was longest on RAL [33.4 months interquartile range (16.7–48.3)], compared with EVG/c [17.7 (7.6–31.7)] and DTG [17.1 (8.5–26.2)]. During follow-up, 2105 (21.7%) persons discontinued an INSTI; 619 (12.3%) discontinued DTG, 341 (17.6%) discontinued EVG/c, and 1145 (42.1%) discontinued RAL. Among those discontinuing, median time to discontinuation was 6.3 months (2.7–14.0) on DTG, 8.9 (3.2–18.4) on EVG/c, and 12.2 (4.4–24.0) on RAL.

KM plots of discontinuation, overall and by ART-experience are shown in Figure 1. The overall KM estimate of discontinuation at 6 months after INSTI start was 8.9% (95% confidence interval: 8.3 to 9.5) and highest on RAL [14.0% (12.7 to 15.4) vs 6.4% (5.7 to 7.2) on DTG, 7.4% (6.3 to 8.8) on EVG/c; P < 0.001], and this was consistent between ART-naive, ART-experienced with VL <400 copies/mL, and ART-experienced with VL ≥400 copies/mL. Overall, the KM estimates at 1 and 2 years were 10.0% (9.1 to 10.9) and 15.4% (14.2 to 16.7) for DTG, 13.1% (11.5 to 14.9) and 22.0% (19.7 to 24.5) for EVG/c, and 22.6% (21.0 to 24.3) and 36.7% (34.7 to 38.7) for RAL. Discontinuation of RAL was highest in 2014 and 2015 when DTG and EVG/c were both approved.

FIGURE 1.
FIGURE 1.:
Kaplan–Meier plots of INSTI discontinuation: (A) overall; (B) in ART-naive individuals; (C) in ART-experienced individuals with a VL <400 copies/mL; and (D) in ART-experienced individuals with a VL ≥400 copies/mL.

Reasons for discontinuation overall, within 6 months after INSTI start, and after 6 months after INSTI start are presented in Figure 2A. Of all discontinuations by 6 months, the most commonly reported reason for discontinuation was toxicity (31.4% overall), followed by patient/physician choice (24.6% overall). Reasons for discontinuation were similar for DTG and EVG/c, with toxicity accounting for nearly half of all discontinuations in these groups (44.2% and 42.5% respectively). Conversely, of all discontinuations on RAL, the main reason reported was patient/physician choice (28.6%). Discontinuations for treatment simplification accounted for a considerably higher proportion of discontinuations on RAL compared with DTG or EVG/c (19.8% on RAL, 2.7% on DTG, and 1.6% on EVG/c, P < 0.001). We also compared reasons for discontinuation between men and women and found similar results.

FIGURE 2.
FIGURE 2.:
A, Reasons for INSTI discontinuation; (B) Reasons for toxicity discontinuation; split by discontinuations ≤6 months and >6 months after INSTI start. G-I, gastrointestinal. Discontinuation was not counted if the backbone changed or participants went from a STR to individual components or vice versa, provided the INSTI component of the regimen remained the same. Others include pregnancy, availability of more effective treatment, drug interaction, protocol change, regular treatment termination, end of empiric treatment, structured treatment interruption, and study treatment commenced or completed. Treatment failure includes virological failure, immunological failure, clinical progression, and death; if the discontinuation reason was reported as other causes or unknown and the VL at discontinuation (±3 months) was greater than 400 copies/mL, this was counted as treatment failure. Simplified treatment available includes simplified treatment available and treatment too complex; Toxicity includes abnormal fat redistribution, concern of cardiovascular, hypersensitivity reaction, abdomen or gastrointestinal tract toxicity, nervous system toxicity, kidney toxicity, endocrine system toxicity, and unspecified side effects.

Discontinuations due to toxicity were further broken down and compared between INSTI types (Fig. 2B). Overall 439 persons discontinued an INSTI due to toxicity within 6 months after INSTI initiation. Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% on DTG, 23.4% on EVG/c, and 6.6% on RAL, P < 0.001).

Overall 1322 (13.6%) persons discontinued an INSTI more than 6 months after INSTI initiation: 327 (6.5%) on DTG, 214 (11.1%) on EVG/c, and 781 (28.7%) on RAL. Of those, the most commonly reported reason was patient/physician choice, and this was reported for a similar proportion across all INSTIs (26.0%, 20.6%, and 25.9% on DTG, EVG/c, and RAL, respectively, P = 0.50). Toxicity remained the most common reason for discontinuation of DTG (29.7%) and EVG/c (22.4%), and treatment simplification was the most common reason on RAL (31.1%).

Factors associated with discontinuation within the first 6 months are presented in Figure 3. The adjusted risk of discontinuation was higher for RAL [hazard ratio 3.03, 95% confidence interval: (2.47 to 3.70)] and EVG/c [1.37 (1.10 to 1.69)] compared with DTG. Individuals who started an INSTI later were more likely to discontinue [1.11 per year later (1.04 to 1.18)], as were women [1.28 (1.06 to 1.55)], those with uncontrolled viremia compared with a suppressed VL in ART-experienced persons [1.38 (1.08 to 1.75)], and those with HCV [1.32 (1.06 to 1.66)] or previous non–AIDS-defining malignancy [1.55 (1.13 to 2.12)]. Conversely, those in Southern [0.58 (0.43 to 0.78)] and Eastern Europe [0.31 (0.20 to –0.50)] were less likely to discontinue compared with those in Western Europe. Full results from the univariable and multivariable Cox regression models are presented in Table 2, Supplemental Digital Content 1, https://links.lww.com/QAI/B408. Similar results were seen for discontinuations greater than 6 months after INSTI initiation (data not shown). As post-hoc analyses, we additionally adjusted for body mass index (BMI) in the multivariable model, reran analyses including those starting an INSTI from 2015, and looked at predictors of INSTI discontinuation due to toxicity only; all showed similar results.

FIGURE 3.
FIGURE 3.:
Significant associations between baseline characteristics and INSTI discontinuation in the first 6 months after INSTI start.

We found no evidence that the association between risk of discontinuation by 6 months and INSTI type differed according to ART-experience (P-value for interaction 0.51). Prespecified subgroup analyses showed a significant interaction between INSTI type and age group, shown in Figure 3, Supplemental Digital Content 1, https://links.lww.com/QAI/B408 (P-value for interaction 0.001). Across all age groups, the risk of discontinuation was higher on RAL than on DTG; however, the difference between RAL and DTG decreased slightly in older age groups. There was an increased risk of discontinuation of EVG/c compared with DTG in the oldest age group (≥50 years); however, there was no difference in the risk in lower age groups.

DISCUSSION

To the best of our knowledge, this is one of the first, large-scale studies investigating uptake and discontinuation of INSTIs in real-world settings across Europe and Australia. Despite being recommended as first line therapy in HIV treatment guidelines, scarce data exist on the choice of INSTIs used in real-world settings and data on INSTI discontinuation are typically limited to RCTs and smaller, national observational studies. This analysis of almost 10,000 persons starting an INSTI found that as the year of INSTI start increased, the likelihood of starting RAL or EVG/c decreased compared with DTG, with the greatest decline for RAL. Discontinuation was highest on RAL, mainly because of treatment simplification. Moreover, the proportion of individuals discontinuing due to toxicity was highest on DTG, although this proportion was low across all INSTIs.

Subgroup analyses of INSTI uptake showed that women were more likely to start RAL compared with men in lower age groups, but were less likely to start RAL in older age groups. This may partly be because RAL is recommended in treatment guidelines for pregnant women (or women wishing to conceive), in particular those starting follow-up late or whose VL is not fully suppressed at the third trimester.2,29 In older age groups, treatment simplification may be a higher priority for menopausal women; therefore, regimens containing DTG are likely to be favored over RAL.

Furthermore, our analysis showed that those with HBV coinfection were more likely to start RAL or EVG/c, and those with previous CVD were also more likely to start RAL compared with DTG. Treatment guidelines recommend using a TDF or tenofovir alafenamide-containing regimen in HBV coinfected individuals.2,30,31 After adjustment for NRTI backbone, the association between HBV and choice of INSTI was no longer significant, suggesting the backbone was likely driving this treatment choice rather than the INSTI. ABC has been associated with an increased risk of CVD and is commonly prescribed with DTG.32 However, after adjusting for backbone, the association between CVD and the likelihood of starting RAL remained highly significant suggesting this decision was not driven by ABC.

During follow-up, the risk of discontinuation was significantly higher on RAL compared with DTG or EVG/c, mainly because of treatment simplification. We found that the rate of discontinuation on RAL was higher than reported in previous studies.5,14,25 This is likely because the cut off for follow-up in our study was the end of 2017, which was later than other studies and therefore reflects the increasing availability of newer INSTIs. For all INSTIs, the risk of discontinuation increased with later year of INSTI start, which may be related to the growing availability of postmarketing information on AEs associated with INSTIs and greater availability of treatment options.2,3,14,33–36 In addition, the risk of discontinuation was up to 3 times higher in Western Europe compared with other European regions, which may reflect the wider range of available treatment options in Western Europe.37

The risk of INSTI discontinuation was also higher for women compared with men. This is in line with studies conducted by Hoffman et al38 and Llibre et al,39 who reported an increased risk among women of DTG discontinuation and INSTI discontinuation due to AEs, respectively. Studies have suggested that the higher rates of AEs in women are because of a lower BMI leading to higher drug exposure38,40; however, after adjusting for BMI, there remained a significantly higher risk of discontinuation for women. In addition, we found similar rates of discontinuation due to toxicity for women and men (32% and 31% of discontinuations, respectively). Our results suggest that further research is needed on the safety of INSTIs in women, who are often underrepresented in HIV research. Finally, INSTI users in older age groups were more likely to discontinue EVG/c compared with DTG, likely because of the increased frequency of drug interactions on EVG/c.

The most common reasons for INSTI discontinuation within 6 months after INSTI start were patient/physician choice and toxicity. Of those starting an INSTI, the proportion discontinuing within 6 months because of toxicity was relatively low on all INSTIs (3.9% DTG, 4.0% EVG/c, 6.1% RAL). This is an important and reassuring real-world finding showing that toxicities are not leading to high rates of INSTI discontinuation. The most common individual toxicity was from the nervous system for DTG and EVG/c and from the abdomen/gastrointestinal tract for RAL. This is in line with several observational studies that have reported higher rates of DTG discontinuation due to neuropsychiatric AEs compared with other INSTIs.14,25,38,39,41–43 As is the case with several recent observational studies and case reports,38,39,41–46 our results show a higher rate of discontinuation due to toxicity than reported in RCTs, especially on DTG. This likely reflects the selected population participating in RCTs and reflects the need for further investigation. Beyond 6 months after INSTI initiation, the most common toxicity for EVG/c was renal, likely attributable to the coformulation with TDF in the STR TDF/FTC/EVC/c and the increase in creatinine caused by cobicistat.47

Our study has several limitations. Persons enrolled in RESPOND were not randomly selected, because we prespecified the minimum number of participants on INSTIs to be included in the cohort collaboration, and it is not possible to rule out confounding by indication or to fully adjust for all factors associated with choice and discontinuation of INSTIs. As is common with observational studies, there is a relatively high proportion of missing data, particularly for comorbidities. However, sensitivity analyses using multiple imputation to account for missing data showed similar results. Follow-up for DTG in particular, may still be limited as the data cut-off for this analysis was the end of 2017. The reasons for discontinuation of INSTIs are those reported in patient notes and the proportion of unknown reasons, and the distribution of known reasons, differs considerably between cohorts. Only one reason was provided per discontinuation, and the reasons given are limited, for example, patient/physician choice may cover a wide range of reasons including concerns about toxicity, drug interactions, and adherence; however, we did not have access to any further information. However, all cohorts used the HICDEP standard for reporting and have previously participated in the development of this standard. Finally, we did not collect data on nonantiretroviral treatment or pre-existing mental illness, which may affect the choice and discontinuation risk of INSTIs.

In conclusion, uptake of DTG compared with EVG/c or RAL has increased over calendar time, and more in Western Europe compared with other European regions. INSTI discontinuation was mainly due to toxicity in the first 6 months and patient/physician choice thereafter, but was low overall. Discontinuation was significantly higher for RAL, mainly due to treatment simplification, whereas discontinuation due to nervous system toxicities was highest on DTG. Our findings highlight the need for further research to better understand AEs on INSTIs.

ACKNOWLEDGMENTS

The RESPOND study group: AIDS Therapy Evaluation in the Netherlands Cohort (ATHENA): F. Wit, P. Reiss, M. Hillebregt, Stichting HIV Monitoring (SHM), Amsterdam, Netherlands. The Australian HIV Observational Database (AHOD): M. Law, K. Petoumenas, R. Puhr, UNSW, Sydney, Austalia. Austrian HIV Cohort Study (AHIVCOS): R. Zangerle, H. Appoyer, Medizinische Universität Innsbruck, Innsbruch, Austria. CHU Saint-Pierre: S. De Wit, M. Delforge, Centre de Recherche en Maladies Infectieuses a.s.b.l., Brussels, Belgium. EuroSIDA Cohort: J. Rockstroh, CHIP, Rigshospitalet, RegionH, 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, ASST Santi Paolo e Carlo, Milan, Italy; 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 et Centre Hospitalier Universitaire, Nice, France. PISCIS Cohort Study: J. Casabona, JM. Miro, Centre Estudis Epidemiologics de ITS i VIH de Catalunya (CEEISCAT), Badalona, Spain. Royal Free Hospital Cohort: C. Smith, F. Lampe, Royal Free Hospital, University College London, London, United Kingdom. San Raffaele Scientific Institute: A. Castagna, A. Lazzarin, A. Poli, Università Vita-Salute San Raffaele, Milano, Italy. Swedish InfCare HIV Cohort: A. Sönnerborg, K. Falconer, V. Svedhem, Karolinska University Hospital, Stockholm, Sweden. Swiss HIV Cohort Study (SHCS): H. Günthard, B. Ledergerber, H. Bucher, A. Scherrer, University of Zurich, Zurich, Switzerland. University Hospital Bonn: JC. Wasmuth, J. Rockstroh, Bonn, Germany. University Hospital Cologne: JJ. Vehreschild, G. Fätkenheuer, Cologne, Germany.

RESPOND Executive Committee: A. Mocroft, G. Reilly, J. Rooney, V. Vannappagari, H. Garges, J. Rockstroh, M. Law, C. Smith, S. De Wit, J. Lundgren, H. Günthard.

RESPOND Scientific Steering Committee: J. Lundgren, H. Günthard, J. Kowalska, D. Raben, L. Ryom, A. Mocroft, J. Rockstroh, L. Peters, A. Volny Anne, N. Dedes, N. Chkhartishvili, R. Zangerle, M. Law, F. Wit, C. Necsoi, C. Stephan, C. Pradier, A. D'Arminio Monforte, C. Mussini, A. Bruguera, H. Bucher, A. Sönnerborg, JJ. Vehreschild, C. Smith, A. Castagna, G. Reilly, J. Rooney, V. Vannappagari, H. Garges.

RESPOND Outcomes Scientific Interest Group: L. Ryom, A. Mocroft, B. Neesgaard, L. Greenberg, L. Bansi-Matharu, V. Svedhem-Johansson, F. Wit, K. Grabmeier-Pfistershammer, R. Zangerle, J. Hoy, M. Bloch, D. Braun, A. Calmy, G. Schüttfort, M. Youle, S. De Wit, C. Mussini, S. Zona, A. Castagna, A. Antinori, N. Chkhartishvili, N. Bolokadze, E. Fontas, K. Dollet, C. Pradier, JM. Miro, JM. Llibre, JJ. Vehreschild, C. Schwarze-Zander, JC Wasmuth, J. Rockstroh, K. Petoumenos, M. Law, C. Duvivier, G. Dragovic, R. Radoi, C. Oprea, M. Vasylyev, J. Kowalska, R. Matulionyte, V. Mulabdic, G. Marchetti, E. Kuzovatova, N. Coppola, J. Begovac, I. Aho, S. Martini, H. Bucher, A. Harxhi, T. Wæhre, A. Pharris, A. Vassilenko, G. Fätkenheuer, N. Friis-Møller, J. Bogner, A. Maagaard, E. Jablonowska, D. Elbirt, G. Marrone, C. Leen, C. Wyen, M. Kundro, N. Dedes, E. Dixon Williams, J. Gallant, D. Thorpe, V. Vannappagari, H. Garges.

RESPOND Staff: Coordinating Centre Staff: D. Raben, L. Peters, L. Ryom, B. Neesgaard, JF. Larsen, ML. Jakobsen, T. Bruun, A. Bojesen, P. Iversen, EV. Hansen, TW. Elsing. Statistical Staff: A. Mocroft, L. Greenberg. We are grateful for input from the European AIDS Treatment Group.

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Keywords:

HIV; integrase inhibitors; dolutegravir; raltegravir; elvitegravir; toxicity

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