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Abstract

Objectives

To evaluate the durability of three integrase strand transfer inhibitors (INSTIs) and two NRTIs in ART-naive individuals.

Methods

The study design was observational. Patients were HIV-positive, ART-naive subjects starting raltegravir, elvitegravir/cobicistat or dolutegravir with two NRTIs. The primary endpoint was time to treatment failure, i.e. occurrence of virological failure (first of two consecutive plasma HIV RNAs  ≥200 copies/mL after 24 weeks) or INSTI discontinuation for any reason apart from simplification. Secondary endpoints were INSTI discontinuation due to toxicity/intolerance and CD4 count response. Survival analysis was done using Kaplan–Meier and Cox regression.

Results

Two thousand and sixteen patients were included: 310 (15.4%) started raltegravir-based regimens, 994 (49.3%) started dolutegravir-based regimens and 712 (35.3%) started elvitegravir/cobicistat-based regimens. Over a median of 11 months, 167 patients experienced treatment failure; the 1 year probability of treatment failure was 6.5% for raltegravir, 5.4% for dolutegravir and 6.7% for elvitegravir/cobicistat (P = 0.001). Sixty-eight patients (3.4%) discontinued INSTIs owing to toxicity/intolerance. By multivariable analysis, patients starting raltegravir had a 2.03-fold (95% CI = 1.2–3.2) higher risk and patients on elvitegravir/cobicistat a 1.88-fold (95% CI = 1.2–2.9) higher risk of treatment failure versus dolutegravir; there was no difference in risk of discontinuation due to toxicity/intolerance when comparing dolutegravir and raltegravir and marginal evidence for a difference when comparing elvitegravir/cobicistat and dolutegravir (adjusted relative hazard = 1.94 for elvitegravir/cobicistat versus dolutegravir, 95% CI = 1.00–3.76, P = 0.05).

Conclusions

In our real-life setting, INSTI-based regimens showed high potency and durability. Among regimens currently recommended in Europe, those including dolutegravir are associated with a lower risk of treatment failure.

Introduction

Integrase strand transfer inhibitor (INSTI)-based combination regimens are now recommended as the first choice for initial HIV therapy in international and national guidelines.1–3

Each of the three currently licenced drugs in Italy, raltegravir, elvitegravir/cobicistat and dolutegravir, in association with two NRTIs, proved to be equivalent or superior to the standard of care in randomized clinical trials.4–7

Dolutegravir at 50 mg once daily was found to be virologically non-inferior to raltegravir at 400 mg twice daily in combination with two NRTIs over 96 weeks in the SPRING-2 trial;8 there are no randomized trials comparing the response to elvitegravir/cobicistat-based combination ART (cART) with any of the other licenced INSTIs.

We aimed to compare, in a real-life setting, the durability of all three INSTIs in combination with two NRTIs in previously cART-naive HIV-positive individuals.

Patients and methods

All the HIV-positive individuals enrolled in the ICONA Foundation Study cohort, who started their first ever cART regimen with raltegravir, elvitegravir/cobicistat or dolutegravir with two NRTIs after 1 January 2011 (date of licencing in Italy of first INSTI) were included. Data were frozen for analysis on 30 June 2018.

The ICONA cohort was set up in Italy in January 1997. Details of the cohort protocol are described elsewhere.9 The Icona study has been approved by the ethics committees of participating centres; each participant signed an informed consent to be enrolled in the study. The main reason for discontinuing each drug is recorded in the ICONA database as: simplification/proactive switch [either the reduction of drugs or the decrease in daily doses/pills, while viral load (VL) is undetectable], toxicity/intolerance (either side effects or demonstrated toxicity of the drug), failure (either virological, immunological, clinical or death), adherence issues and unknown/other causes.

In this analysis, patients were included if they started tenofovir disoproxil fumarate or tenofovir alafenamide/emtricitabine in combination with raltegravir, or with dolutegravir, or in combination with elvitegravir/cobicistat in a single-tablet regimen [tenofovir disoproxil fumarate (tenofovir alafenamide)/emtricitabine/elvitegravir/cobicistat], or if they started abacavir/lamivudine in combination with raltegravir or with dolutegravir (either single-tablet regimen or not) from being ART-naive and had at least one clinical visit and a VL measurement after starting.

Characteristics of participants at the time of initiating cART, according to the INSTI started, were compared by the χ2 test and the Kruskal–Wallis test when appropriate.

The primary endpoint was the time to treatment failure, defined as the occurrence of virological failure (at the time of the first of two consecutive HIV RNA plasma levels ≥200 copies/mL after 24 weeks) or treatment discontinuation of the INSTI component of the regimen for any reason apart from simplification.10

Secondary endpoints were the time to discontinuation of the INSTI component because of toxicity/intolerance and CD4 count response, as mean CD4 count changes at 6, 12 and 24 months (time windows ±3 months from the index dates) from starting cART, by means of analysis of covariance (ANCOVA), insisting on times in which HIV RNA remained ≤50 copies/mL and correcting the P values for multiple testing (false discovery rate adjustment).

Survival analysis was employed to estimate the incidence of primary and secondary endpoints and to compare responses to INSTI-based regimens. Participant follow-up accrued from the date of starting INSTI-based cART to the estimated date of a failure-defining event or the participant’s last VL measurement, last clinical visit or death. Kaplan–Meier curves and Cox regression models were employed. In a sensitivity analysis, inverse probability-of-censoring weights were used instead of assuming non-informative censoring. The analysis was conducted according to the intention-to-treat (ITT) principle.

Results

Patient characteristics

A total of 2016 patients were included: 310 (15.4%) started raltegravir-based cART, 994 (49.3%) started dolutegravir-based cART and 712 (35.3%) started elvitegravir/cobicistat-based cART. Patients who started raltegravir did so in earlier calendar years and were slightly older (median age = 39 years, versus 36 years for dolutegravir and 37 years for elvitegravir/cobicistat, P = 0.002); a lower proportion were homosexual contacts (44.5%, versus 55.5% for dolutegravir and 56.9% for elvitegravir/cobicistat, P = 0.002) and a higher proportion were coinfected with HCV (8.7%, versus 4.9% for dolutegravir and 5.8% for elvitegravir/cobicistat, P < 0.001) and HBV (1.3%, versus 0.4% for dolutegravir and 1.3% for elvitegravir/cobicistat, P < 0.001). They were also in a more advanced HIV disease stage (Table 1).

Table 1.
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Patient characteristics according to the different INSTI-containing regimens

CharacteristicsRegimen started
raltegravir based, N = 310dolutegravir based, N = 994elvitegravir/ cobicistat based, N = 712Patotal, N = 2016
Female, n (%)67 (21.6)167 (16.8)115 (16.2)0.088349 (17.3)
Age (years), median (IQR)39 (31–47)36 (27–41)37 (28–44)0.00237 (28–44)
Mode of HIV transmission, n (%)0.002
 IVDUs21 (6.8)44 (4.4)38 (5.3)103 (5.1)
 homosexual contacts138 (44.5)552 (55.5)405 (56.9)1095 (54.3)
 heterosexual contacts133 (42.9)322 (32.4)231 (32.4)686 (34.0)
 other/unknown18 (5.8)76 (7.6)38 (5.3)132 (6.5)
Not Italian, n (%)62 (20.0)218 (21.9)170 (23.9)0.075450 (22.3)
Calendar year of baseline, median (IQR)2015 (2014–16)2016 (2016–17)2016 (2015–16)<0.0012016 (2015–17)
HBsAg positive, n (%)4 (1.3)4 (0.4)9 (1.3)<0.00117 (0.8)
HCVAb positive, n (%)27 (8.7)49 (4.9)41 (5.8)<0.001117 (5.8)
AIDS diagnosis, n (%)26 (8.4)48 (4.8)26 (3.7)0.006100 (5.0)
CD4 count (cells/mm3), median (IQR)330 (133–494)343 (121–548)380 (225–553)<0.001356 (151–540)
CD4 count ≤200 cells/mm3, n (%)b107 (35.4)326 (33.3)162 (22.9)<0.001595 (29.9)
CD8 count (cells/mm3), median (IQR)852 (553–1214)853 (542–1251)900 (648–1325)0.018867 (588–1272)
VL (log10 copies/mL), median (IQR)4.93 (4.23–5.43)4.73 (4.10–5.31)4.71 (4.18–5.13)0.0894.75 (4.14–5.27)
Time from HIV diagnosis to starting cART (months), median (IQR)2 (1–9)1 (1–3)2 (1–8)<0.0012 (1–5)
NRTIs started, n (%)<0.001
 abacavir + lamivudine43 (13.9)527 (53.0)0 (0.0)570 (28.3)
 tenofovir disoproxil fumarate + emtricitabine267 (86.1)375 (37.7)594 (83.4)1236 (61.3)
 tenofovir alafenamide + emtricitabine0 (0.0)92 (9.3)118 (16.6)210 (10.4)
CharacteristicsRegimen started
raltegravir based, N = 310dolutegravir based, N = 994elvitegravir/ cobicistat based, N = 712Patotal, N = 2016
Female, n (%)67 (21.6)167 (16.8)115 (16.2)0.088349 (17.3)
Age (years), median (IQR)39 (31–47)36 (27–41)37 (28–44)0.00237 (28–44)
Mode of HIV transmission, n (%)0.002
 IVDUs21 (6.8)44 (4.4)38 (5.3)103 (5.1)
 homosexual contacts138 (44.5)552 (55.5)405 (56.9)1095 (54.3)
 heterosexual contacts133 (42.9)322 (32.4)231 (32.4)686 (34.0)
 other/unknown18 (5.8)76 (7.6)38 (5.3)132 (6.5)
Not Italian, n (%)62 (20.0)218 (21.9)170 (23.9)0.075450 (22.3)
Calendar year of baseline, median (IQR)2015 (2014–16)2016 (2016–17)2016 (2015–16)<0.0012016 (2015–17)
HBsAg positive, n (%)4 (1.3)4 (0.4)9 (1.3)<0.00117 (0.8)
HCVAb positive, n (%)27 (8.7)49 (4.9)41 (5.8)<0.001117 (5.8)
AIDS diagnosis, n (%)26 (8.4)48 (4.8)26 (3.7)0.006100 (5.0)
CD4 count (cells/mm3), median (IQR)330 (133–494)343 (121–548)380 (225–553)<0.001356 (151–540)
CD4 count ≤200 cells/mm3, n (%)b107 (35.4)326 (33.3)162 (22.9)<0.001595 (29.9)
CD8 count (cells/mm3), median (IQR)852 (553–1214)853 (542–1251)900 (648–1325)0.018867 (588–1272)
VL (log10 copies/mL), median (IQR)4.93 (4.23–5.43)4.73 (4.10–5.31)4.71 (4.18–5.13)0.0894.75 (4.14–5.27)
Time from HIV diagnosis to starting cART (months), median (IQR)2 (1–9)1 (1–3)2 (1–8)<0.0012 (1–5)
NRTIs started, n (%)<0.001
 abacavir + lamivudine43 (13.9)527 (53.0)0 (0.0)570 (28.3)
 tenofovir disoproxil fumarate + emtricitabine267 (86.1)375 (37.7)594 (83.4)1236 (61.3)
 tenofovir alafenamide + emtricitabine0 (0.0)92 (9.3)118 (16.6)210 (10.4)

HBsAg, hepatitis B surface antigen; HCVAb, anti-hepatitis C virus antibody test.

a

χ2 or Kruskal–Wallis test as appropriate.

b

29 Cases with missing CD4 cell count.

Table 1.
Open in new tab

Patient characteristics according to the different INSTI-containing regimens

CharacteristicsRegimen started
raltegravir based, N = 310dolutegravir based, N = 994elvitegravir/ cobicistat based, N = 712Patotal, N = 2016
Female, n (%)67 (21.6)167 (16.8)115 (16.2)0.088349 (17.3)
Age (years), median (IQR)39 (31–47)36 (27–41)37 (28–44)0.00237 (28–44)
Mode of HIV transmission, n (%)0.002
 IVDUs21 (6.8)44 (4.4)38 (5.3)103 (5.1)
 homosexual contacts138 (44.5)552 (55.5)405 (56.9)1095 (54.3)
 heterosexual contacts133 (42.9)322 (32.4)231 (32.4)686 (34.0)
 other/unknown18 (5.8)76 (7.6)38 (5.3)132 (6.5)
Not Italian, n (%)62 (20.0)218 (21.9)170 (23.9)0.075450 (22.3)
Calendar year of baseline, median (IQR)2015 (2014–16)2016 (2016–17)2016 (2015–16)<0.0012016 (2015–17)
HBsAg positive, n (%)4 (1.3)4 (0.4)9 (1.3)<0.00117 (0.8)
HCVAb positive, n (%)27 (8.7)49 (4.9)41 (5.8)<0.001117 (5.8)
AIDS diagnosis, n (%)26 (8.4)48 (4.8)26 (3.7)0.006100 (5.0)
CD4 count (cells/mm3), median (IQR)330 (133–494)343 (121–548)380 (225–553)<0.001356 (151–540)
CD4 count ≤200 cells/mm3, n (%)b107 (35.4)326 (33.3)162 (22.9)<0.001595 (29.9)
CD8 count (cells/mm3), median (IQR)852 (553–1214)853 (542–1251)900 (648–1325)0.018867 (588–1272)
VL (log10 copies/mL), median (IQR)4.93 (4.23–5.43)4.73 (4.10–5.31)4.71 (4.18–5.13)0.0894.75 (4.14–5.27)
Time from HIV diagnosis to starting cART (months), median (IQR)2 (1–9)1 (1–3)2 (1–8)<0.0012 (1–5)
NRTIs started, n (%)<0.001
 abacavir + lamivudine43 (13.9)527 (53.0)0 (0.0)570 (28.3)
 tenofovir disoproxil fumarate + emtricitabine267 (86.1)375 (37.7)594 (83.4)1236 (61.3)
 tenofovir alafenamide + emtricitabine0 (0.0)92 (9.3)118 (16.6)210 (10.4)
CharacteristicsRegimen started
raltegravir based, N = 310dolutegravir based, N = 994elvitegravir/ cobicistat based, N = 712Patotal, N = 2016
Female, n (%)67 (21.6)167 (16.8)115 (16.2)0.088349 (17.3)
Age (years), median (IQR)39 (31–47)36 (27–41)37 (28–44)0.00237 (28–44)
Mode of HIV transmission, n (%)0.002
 IVDUs21 (6.8)44 (4.4)38 (5.3)103 (5.1)
 homosexual contacts138 (44.5)552 (55.5)405 (56.9)1095 (54.3)
 heterosexual contacts133 (42.9)322 (32.4)231 (32.4)686 (34.0)
 other/unknown18 (5.8)76 (7.6)38 (5.3)132 (6.5)
Not Italian, n (%)62 (20.0)218 (21.9)170 (23.9)0.075450 (22.3)
Calendar year of baseline, median (IQR)2015 (2014–16)2016 (2016–17)2016 (2015–16)<0.0012016 (2015–17)
HBsAg positive, n (%)4 (1.3)4 (0.4)9 (1.3)<0.00117 (0.8)
HCVAb positive, n (%)27 (8.7)49 (4.9)41 (5.8)<0.001117 (5.8)
AIDS diagnosis, n (%)26 (8.4)48 (4.8)26 (3.7)0.006100 (5.0)
CD4 count (cells/mm3), median (IQR)330 (133–494)343 (121–548)380 (225–553)<0.001356 (151–540)
CD4 count ≤200 cells/mm3, n (%)b107 (35.4)326 (33.3)162 (22.9)<0.001595 (29.9)
CD8 count (cells/mm3), median (IQR)852 (553–1214)853 (542–1251)900 (648–1325)0.018867 (588–1272)
VL (log10 copies/mL), median (IQR)4.93 (4.23–5.43)4.73 (4.10–5.31)4.71 (4.18–5.13)0.0894.75 (4.14–5.27)
Time from HIV diagnosis to starting cART (months), median (IQR)2 (1–9)1 (1–3)2 (1–8)<0.0012 (1–5)
NRTIs started, n (%)<0.001
 abacavir + lamivudine43 (13.9)527 (53.0)0 (0.0)570 (28.3)
 tenofovir disoproxil fumarate + emtricitabine267 (86.1)375 (37.7)594 (83.4)1236 (61.3)
 tenofovir alafenamide + emtricitabine0 (0.0)92 (9.3)118 (16.6)210 (10.4)

HBsAg, hepatitis B surface antigen; HCVAb, anti-hepatitis C virus antibody test.

a

χ2 or Kruskal–Wallis test as appropriate.

b

29 Cases with missing CD4 cell count.

Primary endpoint: treatment failure

Over a median follow-up of 11 (IQR = 3–20) months (raltegravir 15, dolutegravir 9 and elvitegravir/cobicistat 11), a total of 167 failures were observed, resulting in an estimated 1 year risk of treatment failure of 6.5% (95% CI = 3.6–9.5) for raltegravir, 5.4% (95% CI = 3.7–7.0) for dolutegravir and 6.7% (95% CI = 4.6–8.7) for elvitegravir/cobicistat (P = 0.001). Results were similar after relaxing the assumption of non-informative censoring by using inverse probability-of-censoring weighting survival curves and when comparing specific regimens, accounting also for the exact NRTI pair used in combination (Figure S1, available as Supplementary data at JAC Online).

Secondary endpoints

A total of 246/2016 (12.2%) patients discontinued the INSTI component of their regimen: 39.0% of patients on raltegravir, 5.5% of patients on dolutegravir and 9.8% of patients on elvitegravir/cobicistat. Raltegravir was stopped mainly due to proactive switch (62.8% of discontinuations), whereas both dolutegravir and elvitegravir/cobicistat were discontinued mainly due to toxicity/intolerance (47.3% and 44.3% of discontinuations, respectively). In patients on dolutegravir, discontinuation due to neuropsychiatric symptoms occurred in a total of 13 cases (1.3%) (see Table S1).

Sixty-eight patients (3.4% of total) discontinued the INSTI component of the regimen due to toxicity/intolerance; the 1 year probability of discontinuation due to intolerance/toxicity was 3.5% (95% CI = 0.7–6.2) for raltegravir-based regimens, 3.7% (95% CI = 2.2–5.1) for dolutegravir and 4.2% (95% CI = 2.6–5.9) for elvitegravir/cobicistat (P = 0.34).

CD4 count change from pre-ART levels

After controlling for pre-ART CD4 count level, and other potential confounders from fitting an ANCOVA regression model and for a given VL ≤ 50 copies/mL, current CD4 counts showed larger increases with longer time from ART initiation, with the largest CD4 count changes seen in people who started dolutegravir, followed by elvitegravir/cobicistat and then raltegravir at all three studied timepoints (see Table S2).

Table 2.
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Relative hazards of reaching the endpoints by univariate and multivariate Cox analyses

OutcomesUnadjusted and adjusted relative hazards
unadjusted relative hazard (95% CI)Padjusteda relative hazard (95% CI)P
Treatment failure
 raltegravir based2.03 (1.36–3.03)<0.0012.00 (1.24–3.21)0.004
 dolutegravir based1.001.00
 elvitegravir/cobicistat based1.61 (1.12–2.31)0.0111.88 (1.20–2.95)0.006
Discontinuation due to toxicity
 raltegravir based1.33 (0.66–2.68)0.4191.55 (0.69–3.50)0.286
 dolutegravir based1.001.00
 elvitegravir/cobicistat based1.43 (0.87–2.34)0.1541.94 (1.00–3.76)0.051
OutcomesUnadjusted and adjusted relative hazards
unadjusted relative hazard (95% CI)Padjusteda relative hazard (95% CI)P
Treatment failure
 raltegravir based2.03 (1.36–3.03)<0.0012.00 (1.24–3.21)0.004
 dolutegravir based1.001.00
 elvitegravir/cobicistat based1.61 (1.12–2.31)0.0111.88 (1.20–2.95)0.006
Discontinuation due to toxicity
 raltegravir based1.33 (0.66–2.68)0.4191.55 (0.69–3.50)0.286
 dolutegravir based1.001.00
 elvitegravir/cobicistat based1.43 (0.87–2.34)0.1541.94 (1.00–3.76)0.051
a

Adjusted for age, gender, nation of birth, mode of HIV transmission, hepatitis coinfection status, AIDS diagnosis, baseline CD4 count, VL and year of starting cART.

Table 2.
Open in new tab

Relative hazards of reaching the endpoints by univariate and multivariate Cox analyses

OutcomesUnadjusted and adjusted relative hazards
unadjusted relative hazard (95% CI)Padjusteda relative hazard (95% CI)P
Treatment failure
 raltegravir based2.03 (1.36–3.03)<0.0012.00 (1.24–3.21)0.004
 dolutegravir based1.001.00
 elvitegravir/cobicistat based1.61 (1.12–2.31)0.0111.88 (1.20–2.95)0.006
Discontinuation due to toxicity
 raltegravir based1.33 (0.66–2.68)0.4191.55 (0.69–3.50)0.286
 dolutegravir based1.001.00
 elvitegravir/cobicistat based1.43 (0.87–2.34)0.1541.94 (1.00–3.76)0.051
OutcomesUnadjusted and adjusted relative hazards
unadjusted relative hazard (95% CI)Padjusteda relative hazard (95% CI)P
Treatment failure
 raltegravir based2.03 (1.36–3.03)<0.0012.00 (1.24–3.21)0.004
 dolutegravir based1.001.00
 elvitegravir/cobicistat based1.61 (1.12–2.31)0.0111.88 (1.20–2.95)0.006
Discontinuation due to toxicity
 raltegravir based1.33 (0.66–2.68)0.4191.55 (0.69–3.50)0.286
 dolutegravir based1.001.00
 elvitegravir/cobicistat based1.43 (0.87–2.34)0.1541.94 (1.00–3.76)0.051
a

Adjusted for age, gender, nation of birth, mode of HIV transmission, hepatitis coinfection status, AIDS diagnosis, baseline CD4 count, VL and year of starting cART.

Independent predictors of primary and secondary endpoints

Compared with patients who started dolutegravir-based regimens and after adjusting for a number of confounders (specified in the footnote of Table 2), patients who started raltegravir-containing regimens had a 2.0-fold (95% CI = 1.2–3.2) higher risk of treatment failure and those who started elvitegravir/cobicistat had a 1.88-fold (95% CI = 1.2–2.9) higher risk of failure (P = 0.004).

There was no evidence of a difference in the risk of discontinuation due to toxicity/intolerance when comparing dolutegravir and raltegravir (adjusted relative hazard = 1.55 for raltegravir versus dolutegravir, 95% CI = 0.69–3.50, P = 0.29) and marginal evidence of a difference in those starting elvitegravir/cobicistat versus dolutegravir (adjusted relative hazard = 1.94 for elvitegravir/cobicistat versus dolutegravir, 95% CI = 1.00–3.76, P = 0.05) (Table 2).

These results were confirmed when restricting the analysis to patients who started tenofovir disoproxil fumarate or tenofovir alafenamide/emtricitabine backbone (data not shown).

Discussion

Our analysis from a large dataset of HIV-positive patients seen for HIV care in Italy confirms that INSTI-based regimens, used as initial therapy with either tenofovir disoproxil fumarate or tenofovir alafenamide/emtricitabine or abacavir/lamivudine, are very potent and well-tolerated regimens associated with very few failure events; over 1 year of follow-up, only 246 out of 2016 (12.2%) patients discontinued their INSTI regimen for any reason, 68 (3.4%) patients discontinued due to toxicity and only 13 (0.6%) showed evidence of virological failure. In our real-life setting, dolutegravir-based regimens showed superiority over the other two regimens with regard to the composite endpoint of treatment failure. The difference in durability appeared to be reflected also in a marginal difference in CD4 count response. Our data are not completely consistent with those of the SPRING trial,8 in which raltegravir showed virological non-inferiority and the same rate of discontinuations due to adverse events.

All the studied regimens were well tolerated, with only a marginally significant difference between elvitegravir/cobicistat and dolutegravir, but only for toxicity-related discontinuations. The rate of discontinuation due to adverse events of all the INSTI-based regimens has also been shown to be very low (less than 2% at 48 weeks) in fully powered randomized clinical trials.4–8 In our clinical setting, the rate of discontinuation due to toxicity/intolerance was slightly higher at 3.5%, 3.7% and 4.2% for raltegravir, dolutegravir and elvitegravir/cobicistat, respectively, over a median of one year of follow-up. Interestingly, discontinuation due to neuropsychiatric symptoms occurred in only 13 cases, i.e. 1.3% of all patients on dolutegravir, which is consistent with the results shown in a similar analysis of the Swiss HIV cohort study (1.7% neuropsychiatric toxicity).11 However, this rate is considerably lower compared with that shown in other observational studies showing rates of dolutegravir interruptions ranging from 7.6% to 13.7%.12–14

Gastrointestinal intolerance was the main cause of discontinuation due to toxicity/intolerance in participants who started elvitegravir/cobicistat-based regimens (29%), followed by renal toxicity (19%), also confirming the data from clinical trials.5 Renal toxicity can be attributable mainly to the combined use of any INSTI with tenofovir disoproxil fumarate.15

Some limitations of this analysis need to be mentioned. First, we cannot exclude that the differences found could be due to unmeasured confounding. Also, our analysis could be biased against elvitegravir/cobicistat. This is because, unlike dolutegravir, elvitegravir/cobicistat is always given as a single-tablet regimen in co-formulation with NRTIs.

In conclusion, in our real-life population, we demonstrated high efficacy and tolerability of all studied INSTI-based regimens currently available in Europe and a lower risk of treatment failure in those using dolutegravir.

Acknowledgements

Members of the ICONA Foundation Study Group

Board of directors: A. d’Arminio Monforte (President), A. Antinori (Vice-President), M. Andreoni, A. Castagna, F. Castelli, R. Cauda, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, G. C. Marchetti, G. Rezza, F. von Schloesser and 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 and C. F. Perno.

Steering committee: A. Antinori, C. Balotta, A. Bandera, S. Bonora, M. Borderi, A. Calcagno, A. Capetti, M. R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, S. Cicalini, 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, L. Monno, C. Mussini, S. Nozza, C. F. Perno, C. Pinnetti, M. Puoti, E. Quiros Roldan, R. Rossotti, S. Rusconi, M. M. Santoro, A. Saracino and L. Sarmati.

Statistical and monitoring team: A. Cozzi-Lepri, I. Fanti, L. Galli, P. Lorenzini, A. Rodanò’, M. Macchia and A. Tavelli.

Biological bank INMI: F. Carletti, S. Carrara, A. Di Caro, S. Graziano, F. Petrone, G. Prota, S. Quartu and S. Truffa.

Participating physicians and centres: Italy: A. Giacometti, A. Costantini and V. Barocci (Ancona); G. Angarano, L. Monno and C. Fabrizio (Bari); F. Maggiolo and C. Suardi (Bergamo); P. Viale, V. Donati and G. Verucchi (Bologna); F. Castelnuovo, C. Minardi and E. Quiros Roldan (Brescia); B. Menzaghi and C. Abeli (Busto Arsizio); B. Cacopardo and B. Celesia (Catania); J. Vecchiet and K. Falasca (Chieti); A. Pan and S. Lorenzotti (Cremona); L. Sighinolfi and D. Segala (Ferrara); P. Blanc and F. Vichi (Firenze); G. Cassola, C. Viscoli, A. Alessandrini, N. Bobbio and G. Mazzarello (Genova); M. Lichtner and I. Pozzetto (Latina); P. Bonfanti and C. Molteni (Lecco); A. Chiodera and P. Milini (Macerata); G. Nunnari and G. Pellicanò (Messina); A. d’Arminio Monforte, M. Galli, A. Lazzarin, G. Rizzardini, M. Puoti, A. Castagna, F. Bai, M. C. Moioli, R. Piolini, A. L. Ridolfo, S. Salpietro and C. Tincati (Milano); C. Mussini and C. Puzzolante (Modena); C. Migliorino and G. Lapadula (Monza); V. Sangiovanni, G. Borgia, V. Esposito, F. Di Martino, I. Gentile and L. Maddaloni (Napoli); A. M. Cattelan and S. Marinello (Padova); A. Cascio and C. Colomba (Palermo); F. Baldelli and E. Schiaroli (Perugia); G. Parruti and F. Sozio (Pescara); G. Magnani and M. A. Ursitti (Reggio Emilia); M. Andreoni, A. Antinori, R. Cauda, A. Cristaudo, V. Vullo, R. Acinapura, G. Baldin, M. Capozzi, A. Mondi, A. Cingolani, M. Rivano Capparucia, G. Iaiani, A. Latini, R. Gagliardini, M. M. Plazzi, S. Savinelli and A. Vergori (Roma); M. Cecchetto and F. Viviani (Rovigo); G. Madeddu and P. Bagella (Sassari); A. De Luca and B. Rossetti (Siena); A. Franco and R. Fontana Del Vecchio (Siracusa); D. Francisci and C. Di Giuli (Terni); P. Caramello, G. Di Perri, S. Bonora, G. C. Orofino and M. Sciandra (Torino); M. Bassetti and A. Londero (Udine); G. Pellizzer and V. Manfrin (Vicenza); and G. Starnini and A. Ialungo (Viterbo).

Funding

The ICONA Foundation is supported by unrestricted grants from Gilead Sciences, Janssen, Merck Sharp and Dohme and ViiV Healthcare. All supporters of the ICONA Foundation had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Data for this paper have been collected as part of the routine work of the ICONA Foundation study.

Transparency declarations

None to declare.

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Author notes

†

Members are listed in the Acknowledgements section.

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].
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