Durability of First-Line Antiretroviral Regimens in the era of Integrase Inhibitors: A Cohort of HIV-Positive Individuals in Spain,2014

Abstract

Background

We compared time to treatment change (TC), viral suppression (VS) and change in CD4⁺ T-cell counts of first-line antiretroviral regimens (ART).

Methods

We analysed HIV treatment-naive adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) initiating the most commonly used ART regimens from September 2014 to November 2015. We used proportional hazards models on the sub-distribution hazard to estimate sub-distribution hazard ratios (sHR) for time to TC, logistic regression to estimate odds ratios (ORs) for VS (viral load <50 copies/ml), and linear regression to assess mean differences in CD4⁺ T-cell changes from ART initiation.

Results

Among 960 individuals, tenofovir (TDF)/emtricitabine (FTC)/rilpivirine (RPV) was the most frequently prescribed regimen (24.2%), followed by elvitegravir (EVG)/cobicistat (COBI)/TDF/FTC (22.8%), abacavir (ABC)/lamivudine (3TC)/dolutegavir (DTG; 17.4%), TDF/FTC+darunavir/ritonavir (DRV/r) or darunavir/cobicistat (DRV/c; 12.1%), TDF/FTC/efavirenz (EFV; 8.8%), TDF/FTC+raltegravir (RAL; 7.7%) and TDF/FTC+DTG (7.0%). Initiating ART with TDF/FTC+DRV/r or DRV/c (adjusted sHR: 2.96; 95% CI: 1.44, 6.08), TDF/FTC/EFV (2.18; 0.98, 4.82), TDF/FTC+RAL (2.37; 1.08, 5.22) and TDF/FTC+DTG (6.34; 3.18, 12.64) was associated with a higher risk of TC compared to ABC/3TC/DTG. At 24 weeks, VS was lower in TDF/FTC+DRV/r or DRV/c (adjusted OR: 0.37, 95% CI: 0.18, 0.74) compared with ABC/3TC/DTG, and CD4⁺ T-cell increase was lower in patients initiating with TDF/FTC/RPV (adjusted mean difference: −75.9, 95% CI: −130.6, −21.2) compared with those who did with ABC/3TC/DTG.

Conclusions

Time to TC, VS and change in CD4⁺ T-cell counts varies by initial regimen. These differences may be useful for making decision when initiating ART.

Introduction

Medication persistence is defined as ‘the duration of time from initiation to discontinuation of therapy’. In the literature, the terms persistence and durability are often used to describe the continuation of the initial regimen [1]. Persistence of antiretroviral therapy (ART) is linked to clinical outcomes, as decreased persistence on ART has been associated with lower probability of achieving virological suppression [2]. Among HIV-infected patients, decreased treatment persistence is associated with patient-dependent factors (such as high viral load, low CD4⁺ T-cell count, female gender, younger age, mental diseases, etc) and medication-dependent factors. Regarding medication-dependent factors, in an extensive review, Bae et al. [2] identified adverse effects and treatment failure as the two most frequent reasons for treatment discontinuation in Western countries; other factors associated with the antiretroviral regimen, such as more frequent dosing and higher pill burden have also been linked to decreased persistence [2].

Several research works have investigated the influence of individual antiretroviral medications, or antiretroviral classes, on treatment persistence or durability. Many of these studies, however, lack information on the reasons for treatment discontinuation [1,3,4]. Moreover, most of them were done before the widespread use of newer treatments such as rilpivirine (RPV) or integrase inhibitors. Studies evaluating the durability of treatments based in integrase inhibitors are very scarce, and the evidence is particularly lacking on newer integrase inhibitors such as elvitegravir and dolutegravir (DTG) [1,3,5–9].

The efficacy of different antiretroviral treatments has been well studied in clinical trials. However, these trials include selected patients with characteristics that are different from those of the population who will receive those treatments (such as lower number of patients with severe immunosuppression, elderly patients, or those with comorbidities), limiting the generalizability of their findings. Therefore, it is necessary to contrast the findings from clinical trials with ‘real life’ data, such as those obtained from cohort studies [10,11].

Clinical guidelines provide recommendations for ART in naive patients. However, along with the information from clinical trials, clinicians might find other information from ‘real world’ situations useful in order to make the decision on which treatment to prescribe. The questions asked when prescribing an initial ART can include, among other things, how long can the initial treatment be maintained without having to change it due to lack of effectiveness, adverse side effects or for the need of more convenient regimens. In this study, we aimed to assess the time to treatment change (TC) and reasons for and patterns of TC, viral suppression and change in CD4⁺ T-cell counts of the most frequently prescribed regimens in recent years (2014 and 2015) in HIV-positive patients in the Cohort of the Spanish AIDS Research Network (CoRIS).

Methods

Study design

CoRIS is an open, multicentre and prospective cohort of HIV-positive adults, naive to ART at study entry, seen for the first time from January 2004 in any of the 42 centres from 13 of 17 regions in Spain, and followed-up until 30 November 2015, the administrative censoring date for these analyses. Subjects agree to participate in the study by signing an informed consent form. Ethical approval for CoRIS was granted.

Briefly, CoRIS collects a minimum dataset as provided for in the cohort protocol which includes baseline and follow-up socio-demographic, immunological and clinical data including ART medication, with start and stop dates, as well as reasons for drug discontinuation.

Data are subjected to internal quality control. Patients are followed periodically in accordance with routine clinical practice.

Study population

Patients considered for inclusion were antiretroviral-naive patients, aged ≥18 years, who started ART between 1 September 2014 (when DTG became available in Spain) and 30 November 2015 with the most commonly used first-line antiretroviral regimens. In order to facilitate the analyses, only regimens accounting for >5% of individuals were considered. Patients with no follow-up after initiation of ART were excluded.

Outcomes

The primary outcome was time from ART initiation to treatment change during the first 48 weeks after ART initiation, and the reason for treatment change. Discontinuation of treatment was not classified as treatment change if patients resumed the initial regimen. Reasons for treatment change were classified as simplification, adverse side effect, treatment failure, drug interaction, patient's decision, pregnancy, enrolment in a clinical trial, other and unknown. In turn, adverse side effects were classified as neuropsychiatric (headache, dizziness, fatigue, insomnia, sleep disturbance, anxiety/depression, emotional instability), renal, gastrointestinal (nauseas/vomiting, diarrhoea, abdominal pain), skin, liver, other and unknown.

The secondary outcomes were viral suppression, defined as achieving a viral load ≤50 copies/ml at week 24 (±12) after ART initiation, and the change in CD4⁺ T-cell counts at week 24 (±12) after treatment initiation. Both responses were analysed by initial regimen, independently of later treatment changes and reasons for those.

Statistical analysis

Descriptive analysis of patients’ characteristics was carried out using frequency tables for categorical variables and median and interquartile range for continuous variables. Differences in socio-demographic and clinical characteristics according to initial regimen were assessed with the non-parametric Kruskal-Wallis test for continuous variables and the χ² test for independence for categorical variables.

For the analyses on time to treatment change during the first 48 weeks after ART initiation, an individual's follow-up started at ART initiation and ended at date of treatment change, death, last study contact or after 48 weeks, whichever arose first.

We used the multiple decrement method to calculate the cumulative incidence of treatment change and proportional hazards models on the sub-distribution hazard to estimate sub-distribution hazard ratios (sHR) for treatment change, treating deaths before any treatment change as competing events. Assessment of the proportional sub-hazards assumption was tested for by adding a time-by-treatment interaction term to the models.

Logistic regression models were used to estimate odds ratios (ORs) of association between initial regimen and viral suppression at week 24 (±12). Linear regression models were used to assess differences by initial regimen in mean changes in CD4⁺ T-cell counts at week 24 (±12).

All models were adjusted for the following potential confounders: sex (male, female), age at ART initiation (<30, 30-49, ≥50 years), transmission category (homo/bisexual, heterosexual, other/unknown), educational level (no education or compulsory education, upper secondary or university education, other/unknown), country of origin (Spain, foreign born, unknown), CD4⁺ T-cell count (<200, 200-499, ≥500 cells/μl, unknown) and viral load (<100,000, ≥100,000 copies/ml, unknown) within 6 months previous to ART initiation, presence of HCV antibodies (no, yes, unknown), presence of HBV surface antigen (no, yes, unknown) and AIDS diagnosis at initiation of ART (no, yes).

To adjust for clustering of patients within centres, robust methods were used to estimate standard errors and, thus, to calculate 95% CIs and P-values. Wald tests were used to derive P-values.

All statistical analyses were performed using Stata software (version 14.0; Stata Corporation, College Station, TX, USA).

Results

Of 12,239 patients included in CoRIS by 30 November 2015, 11,279 were excluded from analyses as follows: 2,754 who never initiated ART, 13 aged <18 years at ART initiation, 8,192 who did not start ART between 1 September 2014 and 30 November 2015, 149 with no follow-up after ART initiation and 171 who initiated a treatment prescribed in <5% of patients. Finally, 960 patients were included in the analyses, of which 870 (90.6%) were men, 661 (72.3%) had been infected through homo/bisexual contact and 684 (72.2%) were Spanish. At ART initiation, median age was 37 years (IQR: 30-45), median CD4⁺ T-cell count was 412 cells/μl (247-590), 91 (9.5%) patients had an AIDS diagnosis and 308 (33.8%) had a viral load >100,000 copies/ml. Median follow-up time was 168 days (IQR: 91-272).

The most frequently prescribed initial regimen was tenofovir (TDF)/emtricitabine (FTC)/RPV (n=232, 24.2%), followed by elvitegravir (EVG)/cobicistat (COBI)/TDF/FTC (n=219, 22.8%), abacavir (ABC)/ lamivudine (3TC)/DTG (n=167, 17.4%), TDF/FTC+darunavir/ritonavir (DRV/r) or darunavir/cobicistat (DRV/c; n=116, 12.1%), TDF/FTC/efavirenz (EFV; n=85, 8.8%), TDF/FTC+raltegravir (RAL; n=74, 7.7%) and TDF/FTC+DTG (n=67, 7.0%). There were differences in the sociodemographic and clinical characteristics of patients according to their initial ART regimen (Figure 1). A higher proportion of men infected through homo/bisexual contact had initiated treatment with ABC/3TC/DTG, EVG/COBI/TDF/FTC and TDF/FTC+DTG. The proportion of migrants was considerably higher among those initiating with TDF/FTC/EFV. The highest proportions of patients with less than 200 CD4⁺ T-cells/μl at ART initiation were found among those starting with TDF/FTC+DTG and TDF/FTC+RAL, and the higher proportions of patients with viral load ≥100,000 copies/ml were found among those starting with TDF/FTC+DTG, TDF/FTC+RAL, TDF/FTC/EFV, and TDF/FTC+DRV/r or DRV/c.

Figure 1

Sociodemographic and clinical characteristics at ART initiation according to initial regimen

At 24 weeks from ART initiation, 15.3% of individuals had changed their initial regimen; this proportion ranged from between 8% and 9% in patients initiating with ABC/3TC/DTG, TDF/FTC/RPV and EVG/COBI/TDF/FTC to 46.9%, 25.6% and 23.3% for those who initiated with TDF/FTC+DTG, TDF/FTC+DRV/r or DRV/c and TDF/FTC+RAL, respectively (Figure 2). In multivariable analyses, initiating ART with TDF/FTC+DRV/r or DRV/c (adjusted sHR: 2.96; 95% CI: 1.44, 6.08), TDF/FTC/EFV (adjusted sHR: 2.18; 0.98, 4.82), TDF/FTC+RAL (adjusted sHR: 2.37; 1.08, 5.22) and TDF/FTC+DTG (adjusted sHR: 6.34; 3.18, 12.64) was associated with a higher risk of treatment change during the first 48 weeks after ART initiation compared with ABC/3TC/DTG. However, no significant differences in the risk of treatment change were found between initiating with ABC/3TC/DTG and initiating with TDF/FTC/RPV (adjusted sHR: 1.09; 0.50, 2.37) or EVG/COBI/TDF/FTC (adjusted sHR: 1.22; 0.59, 2.48; Table 1). Median time to treatment change ranged from 53 days (IQR: 28-113) among patients initiating TDF/FTC+DTG to 123 days (IQR: 48-168) for those initiating TDF/FTC+DRV/r or DRV/c.

Figure 2

Cumulative incidence of treatment change according to initial regimen

Table 1

Number of deaths prior any treatment change, number of treatment changes and sub-distribution hazard ratios for the association of initial regimen and the risk of treatment change during first 48 weeks after ART initiation

	Deaths prior any treatment change, n (%)	Treatment changes, n (%)	Univariable analysis		Multivariable analysis^a
	Deaths prior any treatment change, n (%)	Treatment changes, n (%)	sHR (95% CI)	P-value	sHR (95% CI)	P-value
ABC/3TC/DTG	2 (1.2)	12 (7.2)	1.00
TDF/FTC/RPV	1 (0.4)	21 (9.0)	0.91 (0.45, 1.86)	0.80	1.09 (0.50, 2.37)	0.82
EVG/COBI/TDF/FTC	2 (0.9)	22 (10.0)	1.17 (0.58, 2.36)	0.66	1.22 (0.59, 2.48)	0.59
TDF/FTC+DRV/r or DRV/c	2 (1.7)	30 (25.9)	2.76 (1.41, 5.38)	0.003	2.96 (1.44, 6.08)	0.003
TDF/FTC/EFV	0	15 (17.6)	1.80 (0.84, 3.87)	0.13	2.18 (0.98, 4.82)	0.05
TDF/FTC+RAL	1 (1.3)	20 (27.0)	2.67 (1.30, 5.48)	0.008	2.37 (1.08, 5.22)	0.03
TDF/FTC+DTG	0	30 (44.8)	7.16 (3.66, 14.04)	<0.001	6.34 (3.18, 12.64)	<0.001

Adjusted for sex, age at ART initiation, transmission category, educational level, country of origin, CD4+ T-cell count and viral load within 6 months previous to ART initiation, presence of HCV antibodies, presence of HBV surface antigen and AIDS diagnosis at initiation of ART. ABC, abacavir; COBI, cobicistat; DRV/c, darunavir/cobicistat; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; sHR, sub-distribution hazard ratio; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine.

Reasons for discontinuation varied according to the regimen. Overall, 60 (6.2%) patients changed the initial regimen due to simplification, followed by 47 (4.9%) due to an adverse side effect. Treatment failure was the cause of discontinuation in only 12 (1.2%) patients. The highest proportion of patients changing due to simplification was found in TDF/FTC+DTG (35.8%) followed by TDF/FTC+DRV/r or DRV/c (16.4%) and TDF/FTC+RAL (13.5%). The proportion of changes due to adverse side effects was higher among patients starting with TDF/FTC/EFV (14.1%), followed by EVG/COBI/TDF/FTC (5.5%) and TDF/FTC+RAL (5.4%); these three regimens had also the highest proportion of neuropsychiatric adverse side effects (11.8%, 2.7% and 1.3%, respectively; Table 2).

Table 2

Number and percentage of patients changing treatment for each reason according to initial regimen

	ABC/3TC/DTG (n=167)	TDF/FTC/RPV (n=232)	EVG/COBI/TDF/FTC (n=219)	TDF/FTC+DRV/r or DRV/c (n=116)	TDF/FTC/EFV (n=85)	TDF/FTC+RAL (n=74)	TDF/FTC+DTG (n=67)	P-value
Simplification	2 (1.2)	1 (0.4)	3 (1.4)	19 (16.4)	1 (1.2)	10 (13.5)	24 (35.8)	<0.001
Adverse side effect	6 (3.6)	7 (3.0)	12 (5.5)	4 (3.4)	12 (14.1)	4 (5.4)	2 (3.0)	0.004
Neuropsychiatric	1 (0.6)	1 (0.4)	6 (2.7)	0	10 (11.8)	1 (1.3)	0
Renal	0	3 (1.3)	4 (1.8)	1 (0.9)	0	1 (1.3)	1 (1.5)
Gastrointestinal	2 (1.2)	2 (0.9)	5 (2.3)	0	0	1 (1.3)	0
Skin	0	2 (0.9)	1 (0.5)	2 (1.7)	3 (3.5)	1 (1.3)	0
Liver	0	0	0	0	1 (1.2)	0	0
Other	2 (1.2)	0	0	1 (0.9)	1 (1.2)	0	1 (1.5)
Unknown	1 (0.6)	0	0	1 (0.9)	1 (1.2)	0	0
Treatment failure	1 (0.6)	4 (1.7)	2 (0.9)	1 (0.9)	1 (1.2)	1 (1.3)	2 (3.0)	0.81
Drug interaction	1 (0.6)	2 (0.9)	1 (0.5)	2 (1.7)	0	0	1 (1.5)	0.73
Patient's decision	0	2 (0.9)	0	0	0	1 (1.3)	0	0.33
Pregnancy	0	1 (0.4)	1 (0.5)	1 (0.9)	0	0	0	0.86
Enrolment clinical trial	0	0	0	0	0	1 (1.3)	0	0.06
Other	1 (0.6)	4 (1.7)	3 (1.4)	1 (0.9)	1 (1.2)	0	1 (1.5)	0.90
Unknown	1 (0.6)	0	0	2 (1.7)	0	3 (4.1)	0	0.003

ABC, abacavir; COBI, cobicistat; DRV/c, darunavir/cobicistat; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine.

After excluding 60 patients who changed their treatment due to simplification, 9.5% of the patients had changed their treatment at 24 weeks from initiation. When repeating multivariable analysis for the risk of treatment change after excluding those patients, the only regimen that was associated with a higher risk of treatment change after adjusting for potential con-founders was TDF/FTC/EFV (adjusted sHR: 2.67; 95% CI: 1.12, 6.37).

Overall, ABC/3TC/DTG was the most frequently prescribed substitution regimen (41.0%) followed by TDF/FTC/RPV (20.1%) and EVG/COBI/TDF/FTC (8.3%). ABC/3TC/DTG was the preferred substitution regimen for those initiating with TDF/FTC/RPV (30.0%), EVG/COBI/DTF/FTC (45.0%), TDF/FTC+DRV/r or DRV/c (26.7%) and TDF/FTC+DTG (93.3%), while TDF/FTC/RPV was the most frequently selected option to change ABC/3TC/DTG (20.0%), TDF/FTC/EFV (50.0%) and TDF/FTC+RAL (45.0%; data not shown).

Viral suppression and the change in CD4⁺ T-cell counts at 24 weeks after ART initiation were evaluated in 652 (67.9%) and 618 (64.3%) patients who had a viral load and a CD4⁺ T-cell count measurement at week 24 (±12), respectively. At 24 weeks, 83.1% of patients achieved viral suppression, ranging from 71.2% in patients initiating with TDF/FTC+DRV/r or DRV/c to 88.8% among those who did with TDF/FTC/RPV. Among the patients who did not achieve viral suppression at 24 weeks, 79% had viral loads <400 copies/ml. In multivariable analysis, viral suppression at 24 weeks was observed to be lower in patients initiating with TDF/FTC+DRV/r or DRV/c compared with those who did with ABC/3TC/DTG (adjusted OR: 0.37, 95% CI: 0.18, 0.74; Table 3). The mean change in CD4⁺ T-cell counts from baseline to week 24 was 186.4 (95% CI: 168.8, 203.9), being the highest among those initiating with ABC/3TC/DTG (mean increase: 251.0, 95% CI: 205.0, 296.9) and the lowest among those who did with TDF/FTC/RPV (mean increase: 130.8, 95% CI: 98.1, 163.6) cells/μl, respectively. This lower increase in CD4⁺ T-cell counts in patients initiating with TDF/FTC/RPV compared with ABC/3TC/DTG was maintained after adjustment for confounding variables in multivariable analyses (adjusted mean difference: −75.9, 95% CI: −130.6, −21.2; Table 3). Viral suppression and the change in CD4⁺ T-cell counts at 48 weeks were evaluated in a limited number of patients, with results similar to those observed at 24 weeks (data not shown).

Table 3

Viral suppression and change in CD4⁺ T-cell counts at 24 weeks from ART initiation

					Change in CD4⁺ T-cell counts at 24 weeks from ART initiation
	Viral suppression at 24 weeks after ART initiation				Patients with data, n (%)	Mean CD4⁺ T-cell change (95% CI)	Univariable analysis: mean difference in CD4⁺ T-cell change (95% CI)	Multivariable analysis^a: mean difference in CD4⁺ T-cell change (95% CI)
	Patients with data, n (%)	Viral suppression, n (%)	Univariable analysis: OR (95% CI)	Multivariable analysis^a: OR (95% CI)	Patients with data, n (%)	Mean CD4⁺ T-cell change (95% CI)
ABC/3TC/DTG	94 (56.3)	82 (87.2)	1.00	1.00	88 (52.7)	251.0 (205.0, 296.9)	–	–
TDF/FTC/RPV	178 (76.7)	158 (88.8)	1.16 (0.52, 2.56)	0.63 (0.29, 1.37)	173 (74.6)	130.8 (98.1, 163.6)	−120.1 (−161.5, −78.7)	−75.9 (−130.6, −21.2)
EVG/COBI/TDF/FTC	146 (66.7)	122 (83.6)	0.74 (0.33, 1.68)	0.73 (0.34, 1.57)	132 (60.2)	179.9 (142.4, 217.4)	−71.1 (−139.5, −2.7)	−64.9 (−134.5, 4.6)
TDF/FTC+DRV/r or DRV/c	80 (69.0)	57 (71.2)	0.36 (0.18, 0.75)	0.37 (0.18, 0.74)	76 (65.5)	204.1 (154.7, 253.5)	−46.8 (−109.1, 15.4)	−29.6 (−84.9, 25.8)
TDF/FTC/EFV	59 (69.4)	46 (78.0)	0.52 (0.21, 1.25)	0.57 (0.24, 1.36)	54 (63.5)	236.0 (177.4, 294.6)	−15.0 (−107.1, 77.2)	−32.3 (−115.0, 50.5)
TDF/FTC+RAL	52 (70.3)	43 (82.7)	0.70 (0.31, 1.57)	0.83 (0.35, 1.95)	52 (70.3)	196.0 (136.2, 255.7)	−55.0 (−120.6, 10.6)	−30.2 (−95.7, 35.3)
TDF/FTC+DTG	43 (64.2)	34 (79.1)	0.55 (0.25, 1.22)	0.69 (0.27, 1.75)	43 (64.2)	192.0 (126.3, 257.7)	−59.0 (−118.8, 0.8)	−51.1 (−118.5, 16.2)

Adjusted for sex, age at ART initiation, transmission category, educational level, country of origin, CD4+ T-cell count and viral load within 6 months previous to ART initiation, presence of HCV antibodies, presence of HBV surface antigen and AIDS diagnosis at initiation of ART. ABC, abacavir; COBI, cobicistat; DRV/c, darunavir/cobicistat; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine.

Discussion

We have analysed the durability, viral suppression and change in CD4⁺ T-cell counts of the most frequently prescribed initial antiretroviral regimens in recent years in a large multicentre cohort in Spain. TDF/FTC+DRV/r or DRV/c, TDF/FTC/EFV, TDF/FTC+RAL and TDF/FTC+DTG had a significantly lower durability compared with ABC/3TC/DTG, EVG/COBI/TDF/FTC or TDF/FTC/RPV after adjusting for other risk factors. The main reason for treatment modification was simplification (mainly for the regimens TDF/FTC+DTG, TDF/FTC+RAL, and TDF/FTC+DRV/r or DRV/c), followed by adverse side effects; the latter were the main reason for modification of TDF/FTC/EFV. Compared with ABC/3TC/DTG, viral suppression was significantly lower in patients receiving TDF/FTC+DRV/r or DRV/c, and change in CD4⁺ T-cell counts was significantly lower in patients receiving TDF/FTC+RPV. Overall, very few patients modified their treatment due to failure.

We found differences in prescription patterns according to clinical and demographic characteristics. Regimens including integrase inhibitors (mainly DTG and elvitegravir) were more frequently prescribed to men who have sex with men, and TDF/FTC/EFV was more frequently prescribed to immigrants. Although in some cases TDF/FTC/EFV might have been prescribed bearing in mind that it would be available in the immigrant patient's country of origin, this might also suggest inequalities in the access to antiretroviral therapy, as this is the cheapest of all the regimens analysed [12] and also the most poorly tolerated. Antiretroviral therapy is provided free of charge in the Spanish national healthcare system, but there are budget limitations in certain hospitals and Regions.

The 15% overall proportion of treatment modifications at 24 weeks after treatment initiation was similar to the one found in an earlier study of this same cohort (16% during the years 2008–2010), when integrase inhibitors were not part of the initial treatment [13]; our rate in this study might seem high as in these more recent years integrase inhibitors, which are generally better tolerated and more effective than older regimens, are widely used. However, the proportion of patients who modified their treatment was lower (9%) after excluding the patients who changed it due to simplification.

TDF/FTC+DTG, TDF/FTC+RAL, TDF/FTC+DRV/r (or DRV/c), and TDF/FTC/EFV had a significantly higher rate of discontinuation. It is worth noting that, except for TDF/FTC/EFV which was more frequently discontinued due to adverse side effects, all the other regimens were composed of at least two pills a day and were discontinued mainly because of simplification, and all the regimens with higher durability were single treatment regimens. The proportion of discontinuations due to treatment failure was very low overall, which is consistent with the high effectiveness of these newer treatments shown in clinical trials [14]. These findings are consistent with those from a large cohort in the United States, which found very low rates of treatment change associated with virological failure in recent years [15].

To interpret the rates of discontinuation, we must consider some of the reasons why some of these regimens are prescribed. TDF/FTC+DTG and TDF/FTC+RAL, followed by TDF/FTC+DRV/r (or DRV/c) were prescribed to a higher proportion of patients with <200 CD4⁺ T-cells and high viral loads; these were also the regimens with higher rates of discontinuation. Patients with low CD4⁺ T-cell counts need prompt treatment and cannot wait to obtain results from HLA B5701 or resistance testing, and treatments are often prescribed and changed when the results of those tests become available. TDF/FTC+DTG, which had the highest rates of discontinuation, is frequently prescribed pending HLA B5701 test results and subsequently changed to ABC/3TC/DTG, a cheaper and simpler treatment, soon after these results are available, as confirmed by our data. TDF/FTC+RAL is frequently prescribed as first treatment in severely immunosuppressed patients, as it has evidence from clinical trials in this group of patients [16,17], and its low potential for interactions makes it a good alternative for patients that might be receiving other treatments due to opportunistic diseases. Boosted DRV has a high genetic barrier and can be prescribed confidently in patients pending resistance testing. A considerable proportion of these three regimens might have been prescribed in severely immunosuppressed patients with the intention to switch them to more convenient regimens as test results become available or the patient's condition improves.

Whereas studies from earlier years show high rates of discontinuation due to adverse side effects [13,18,19], the treatment was more frequently discontinued due to simplification in this study. Moreover, if TDF/FTC/EFV is excluded, the proportion of patients who modified their treatment due to adverse side effects was less than 6% for all the other regimens studied. This is consistent with the better tolerability of the new drugs and increased availability of regimens with low pill burden, including single treatment regimens, which provide more options for treatment simplification. Among patients starting treatment with TDF/FTC/EFV and EVG/COB/TDF/FTC, the most frequent adverse side effects were neuropsychiatric. It is interesting to note that, despite earlier concerns about DTG neuropsychiatric toxicity [7,20], the proportion of neuropsychiatric events leading to drug discontinuation for the regimens including this drug was very low. This has been also shown in another large cohort study, in which less than 2% of the patients receiving DTG-containing regimens modified their treatment due to neuropsychiatric adverse side effects [5].

Among 652 patients with available data on viral load at 24 weeks, 110 did not achieve viral suppression. However, only 12 patients overall modified their regimen due to virological failure over the study period. This is mainly explained by the fact that the majority of the patients who did not achieve viral suppression had low level viraemia (79% had viral loads <400 copies/ml), which might have led the prescribing physician to maintain the current treatment. We found that TDF/FTC+DRV/r (or DRV/c) had lower viral suppression than ABC/3TC/DTG, confirming the findings from a previous clinical trial [21]. However, it is likely that the observed relative ineffectiveness of TDF/FTC+DRV/r (or DRV/c) is at least partly explained by the fact that, due its high genetic barrier to resistance, this regimen is more often prescribed to patients who have a higher risk of nonadherence. In any case, as discussed previously, only a minority of patients changed their treatment due to virological failure for both regimens (one patient with TDF/FTC+DRV/r [or DRV/c] and one patient with ABC/3TC/DTG).

The regimen TDF/FTC/RPV is not classified as ‘recommended initial therapy for most people living with HIV’ in the DHHS guidelines [14] due to concerns about potential lower effectiveness due to its low genetic barrier. However, we found that in our cohort RPV had high effectiveness and durability, although the change in CD4⁺ T-cell counts with this regimen was lower compared to ABC/3TC/DTG.

The strengths of our study include a large multicentre national cohort with strict data quality control criteria, and the availability of data on the reasons for changing the antiretroviral treatment. Our study findings are limited by the limited follow-up period, which only allows us to evaluate the early treatment changes (before 48 weeks). Furthermore, only around two-thirds of our patients had available data on CD4⁺ T-cell count and viral load at 24 weeks, which limited our analysis of viral suppression and change in CD4⁺ T-cell counts. Also, data on adherence are not available in CoRIS; however, we think this has not been a strong limitation given the low number of treatment changes due to virological failure.

In conclusion, we have evaluated the most frequent initial antiretroviral regimens in a multicentre cohort in Spain, and we have found that durability of antiretroviral treatment varied with the regimen chosen. Overall, simplification was the main reason for treatment modification, followed by adverse side effects; the latter was the main reason for treatment modification for certain regimens, mainly TDF/FTC/EFV. Although viral suppression and the change in CD4⁺ T-cell counts differed between different treatment regimens, lack of durability due to treatment failure was very infrequent for all the regimens studied.

Our study shows that when prescribing initial ART, we can be more confident on the durability of our regimen if we choose a simpler treatment, specially ABC/3TC/DTG, EVG/COBI/TDF/FTC or TDF/FTC/RPV (all available as single tablet regimens). With the newer, more effective and better tolerated regimens analysed, we can also be confident that virological failure or adverse side effects will not influence the continuation of the treatment no matter what regimen we choose, with the exception of TDF/FTC/EFV. This regimen, which is no longer recommended in the guidelines [14,22], had a higher rate of discontinuation due to adverse side effects. These findings might be considered when starting the treatment of naive HIV-infected patients.

Footnotes

Acknowledgements

SM and IJ initiated this project. All authors and CoRIS contributors in the Acknowledgements section and Additional file 1 were involved in data collection and exchange. IJ did the analyses. IJ and ISG drafted the manuscript, which was first reviewed by SM. All authors were involved in the study design, revised the manuscript for important intellectual content and contributed to the final version of the manuscript.

Funding for this study was provided by (i) the Instituto de Salud Carlos III through the Red Tematica de Investigacion Cooperativa en SIDA (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional R+D+I and cofinanced by ISCIII-Subdireccion General de Evaluacion y el Fondo Europeo de Desarrollo Regional (FEDER) and (ii) ViiV Healthcare. ViiV Healthcare was given the opportunity to review a preliminary version of this manuscript for factual accuracy. The authors are solely responsible for final content and interpretation of the results.

Parts of the data were presented at VIII Congreso Nacional de GESIDA 2016, 29 November – 2 December 2016, San Sebastian, Spain.

This study would not have been possible without the collaboration of all the patients, medical and nursery staff, and data managers who have taken part in the project. A list of the centres and investigators involved in CoRIS can be found in Additional file 1.

IJ has received teaching fees from ViiV Healthcare. ISG has received conference grants or speaker fees from BMS, ViiV Healthcare and Gilead. SM has been involved in speaking activities and has received grants for research from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen Cilag, Merck Sharp & Dohme, Pfizer, Roche and Schering Plough. The remaining authors declare no competing interests.

Additional file 1: A list of the centres and investigators involved in CoRIS can be found at

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Durability of First-Line Antiretroviral Regimens in the era of Integrase Inhibitors: A Cohort of HIV-Positive Individuals in Spain,2014–2015

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Study design

Study population

Outcomes

Statistical analysis

Results

Discussion

Footnotes

Acknowledgements

References