https://orcid.org/0000-0003-3186-6416
Abstract
Background
This real-world study compared the safety and effectiveness of Dolutegravir/lamivudine (D/L) and Bictegravir/Emtricitabine/Tenefovir alafenamide (B/F/T) switch therapy regimens for people living with HIV (PLWH)
Methods
The retrospective study conducted from April 2019 to November 2022, included PLWH with < 50 copies/mL of HIV-RNA prior to recruitment who initiated either D/L or B/F/T switching therapy. The primary objective was to evaluate treatment discontinuation rates; safety and virologic outcomes were also evaluated.
Results
690 PLWH were included, 358 in the D/L and 332 in the B/F/T, and a median follow-up of 728 and 1013 days, respectively. The discontinuation proportions were 8.7% (31 participants, incidence rate of 4.44 per 100 PYFU in the D/L group and 15.3% (51 participants, incidence rate of 6.25 per 100 PYFU) in the B/F/T group. The adjusted hazard ratio for B/F/T discontinuation compared to D/L was 1.20 (95% CI: 0.71;2.0; p = 0.494). Virologic failure (VL > 200 copies/mL in two consecutive measurements) occurred in 1.1% and 0.9% of patients in the D/L and B/F/T groups, respectively. Notably, one patient in D/L group with severe non-adherence and virologic failure developed resistance mutations.
Conclusions
Switching to either B/T/F or D/L treatment for PLWH was effective and well tolerated in this real-world study. Treatment discontinuation rates did not significantly differ between the two regimens.
Background
Antiretroviral treatments with Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/T) or Dolutegravir/lamivudine (D/L) are two of the most preferred treatment regimens for people living with HIV (PLWH), These two regimens are among those recommended as first-line options in the guidelines of the United States, United Kingdom, and Europe.Citation1 Their efficacy and safety has been well demonstrated in clinical trials and cohort studies, both in treatment-naïve and -experienced patients.Citation2–5 Only a few cohort studies have compared B/F/T versus D/L in the setting of switching from another therapy.Citation6 The present study aimed to compare the effectiveness and safety of B/F/T versus D/L in a real-world setting.
Methods
Patients
Retrospective single-center study conducted between April of 2019 and November of 2022 at a teaching hospital in Barcelona, Spain. PLWH under follow-up at the HIV unit during this period were included if: (1) had <50 copies/mL of HIV-RNA during at least the 6 months prior to recruitment, and (2) were transitioned from a preexisting therapy to either D/L or B/F/T. There were no exclusion criteria.
Objectives
The primary objective of the study was to compare the rate of treatment discontinuation for any cause between the two treatment groups, D/L and B/F/T. Additionally, safety and virologic outcomes at the end of the follow-up were evaluated. Virological failure was defined by a viral load > 200 copies/mL on two consecutive occasions. Undetectable viremia was considered when the viral load was < 50 copies/mL at any point during follow up.
Statistics
Dichotomous variables were expressed as absolute frequencies and percentages, and continuous variables were reported as means with standard deviations or medians with interquartile range. The chi-square test was used to compare proportions, and the Mann–Whitney U test to compare quantitative variables (p < 0.05 was considered significant). Kaplan–Meier survival analysis was employed to assess and compare the time to treatment discontinuation (TD) between the two treatment groups. The risk of TD was adjusted for various factors, including age, gender, place of birth, risk behaviors for HIV acquisition, and comorbidities using Cox regression analysis. The statistical analysis was conducted using IBM SPSS Statistics for Windows, Version 28 (IMB Corp., Armonk, NY, USA).
The study was approved by the local Ethics Committee (number: 23-10857).
Results
Six hundred ninety PLWH were included. Among them, 358 were switched to D/L (mean age 47.3 years) and 332 to B/F/T (mean age 45.5 years), with a total follow-up of 1.967 and 2.458 PYFU, respectively. Baseline characteristics and differences between groups are summarized in . Approximately 87% of patients were male. Both groups had male predominance. The proportion of non-Spanish PLWH was higher in B/T/F (57.2% vs 50.6% in D/L; p: 0.079). Pre-switch drugs had great variability among groups. 42% of D/L participants previously received Dolutegravir/Abacavir/Lamivudine and were not exposed to new drugs. Furthermore, 80% of the B/T/F group received tenofovir fumarate or tenofovir alafenamide, and every participant received at least one drug that they had not been exposed to. Simplifying the treatment with fewer tablets was the leading switching cause (80% in the D/L group and 35% in the B/F/T group). However, the reasons for switching were more diverse in B/F/T-treated patients.
Table 1. Baseline characteristics and previous treatments.
No substantial differences were found in baseline comorbidities between both groups, except for hepatitis B (0 in the D/L group and 6% in the B/F/T group, p: 0.000). Moreover, approximately half of the patients in both groups had psychiatric disorders, alcohol misuse, drug misuse, or social issues (unstable housing, no fixed address) with slightly higher comorbidity scores in B/F/T ().
Eighty-two participants discontinued treatment after switching: 31 (8.7%) from the D/L group with a total follow-up of 704.37 years (incidence rate of 4.44 per 100 PYFU; 95% CI: 3.50;5.30) and 51 (15.4%) in the B/F/T group with a total follow-up of 815.99 years (incidence rate of 6.25 per 100 PYFU; 95% CI: 4.70;7.89). illustrates the Kaplan–Meier plot displaying the cumulative discontinuation rate. The hazard ratio for discontinuation of B/T/F was 1.28 (95% CI: 0.81;2.02; p = 0.297); the adjusted hazard ratio was 1.20 (95% CI: 0.71–2.0; p: 0.494).
Figure 1. Kaplan–Meier plot of accumulative treatment discontinuation for Dolutegravir/lamivudine (D/L) or Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/T).
The reasons for discontinuation and virological outcomes are detailed in . Adverse events were infrequent (1.9% for D/L and 2.1% for B/F/T). Neuropsychiatric effects leading to D/L treatment discontinuation were present in 0.8% of participants. Weight gain (four patients) and dyslipidemia (two patients) were the most common reasons for B/F/T treatment discontinuation (out of a total of seven patients). Of note, these six patients were previously treated with tenofovir fumarate. When considering only patients not exposed to the same drugs, adverse effects were more frequent in the D/L group compared to B/T/F (2.9% and 0.3%, respectively). Loss to follow-up was more frequent in the B/F/T group (10.5% vs. 5% in D/L-treated patients). No differences in weight gain were observed between the groups.
Table 2. Discontinuation and virologic outcomes.
We did not observe differences in the virological outcome between both groups: 96.4% of D/L-treated PLWH maintained a viral load (VL) of < 50 copies/mL of HIV-RNA versus 96.1% in the B/F/T group; 2.5% in the D/L group had a VL of 51–500 copies/mm3 compared to 3% in B/F/T-treated patients; and virologic failure (considered as two consecutive measurements of > 200 copies/mL) was 1.1% in D/L and 0.9% in the B/F/T group ().
All PLWH with virological failure presented suboptimal adherence to their treatment regimen. Among the 4 D/L-treated PLWH with virological failure, the first one showed an HIV-RNA measurement of 429,358 copies/mL; the second 179,607 copies/mL; the third 257 copies/mL, and the fourth 2,119 copies/mL. In these last two cases, the treatment was discontinued for virological reasons. Among the cohort participants, only the last person developed resistance mutations. This occurrence can be attributed to their low and irregular adherence to the prescribed treatment regimen.
It is essential to provide a more comprehensive explanation of this individual’s situation to better understand the factors that may have contributed to the development of resistance mutations. The individual started ART in 2005 with efavirenz, emtricitabine, and tenofovir disoproxil fumarate. However, due to insomnia issues in late 2017, the ART regimen was switched to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. Around the same time as the medication change, the patient relapsed in alcohol consumption, leading to severe hypertriglyceridemia, hypercholesterolemia, and steatohepatitis. As a result, in January 2018, the decision was made to discontinue ART temporarily. The ART was resumed in June 2018 with a new regimen consisting of dolutegravir, abacavir, and lamivudine, which successfully maintained an undetectable viral load until December 2020, when changed to D/L for simplification. However, in May 2021, the patient experienced another alcohol relapse and subsequently stopped taking ART. From June to September, the patient reported poor adherence to treatment. As a consequence, the HIV-RNA levels increased to 430 copies/mL in October 2021 and further to 440 copies/mL in March 2022. By September 2022, the viral load had risen to 2,119 copies/mL. The genotypic study showed major NRTI (L74V, M184V, K219R) and INSTI mutations (G118R and E138K).
Among the three PLWH in the B/F/T treatment group who experienced viral failure, their plasma viremia levels were measured as follows: 52,381 copies/mL, 44,710 copies/mL, and 236 copies/mL. Despite the detectable viral load, no resistance mutations were identified, and it was decided to maintain them with the same treatment.
Discussion
The present study, including 690 virologically suppressed PLWH demonstrated a similar rate of treatment discontinuation between patients switching to D/L and those switching to B/F/T. Discontinuation due to adverse events was also very similar in both groups (1.9% in D/L and 2.1% in B/F/T). Virological failure was infrequent (approximately 1% for both groups) and appears to be linked to suboptimal treatment adherence.
Our results for the D/L group (8.7% TD after two years of follow-up) are consistent with previous clinical trials, including the TANGO study (14% TD) and the SALSA clinical trial (5% TD).Citation7 Additionally, an Italian cohort study including 785 patients treated with D/L and had longer follow-up period, found a TD rate of 7.5 per 100 PYFU.Citation8 Nevertheless, this study found a higher rate of adverse events leading to TD compared to ours (6.9% vs 1.9%). This difference could be attributable to prior exposure to D/L in our patients, and only adverse events leading to discontinuation were considered. Notably, there may also be differences between physicians’ criteria for treatment discontinuation in clinical practice.
Our results for the B/F/T group (15.4% TD after 2.77 years of follow-up) are also consistent with the existing literature. A multi-center clinical trial observed a TD rate of 6.7%Citation9 and a single-center cohort study in a real-world setting that included 1,371 treatment-experienced PLWH found that 22% discontinued the new treatment after one year.Citation4
TD was often linked to loss of follow-up. Interestingly, we found statistically significant differences between our two groups, 5% TD rate for D/L versus 10.5% for B/F/T. This might be explained by the fact that the B/F/T group had a longer follow-up period. Moreover, the risk factors for sub-optimal adherence and retention in care were more frequent, which could have motivated physicians to consider a potentially more robust three-drug regimen.
Virological outcomes were similar between both groups, with virological failure in 1.1% in D/L and 0.9% in B/F/T. A real-world cohort of patients switched to D/L treatment found that 1.1% presented virological failure.Citation8 Concurrently, in a cohort of PLWH treated with B/F/T, virological failure was reported in 0.6% of patients4. A comparative study with 476 PLWH (350 treated with D/L and 126 with B/F/T) and a 6-month follow-up period did not reveal differences in between groups.Citation6 However, the sample size of this study was smaller, and the follow-up period was shorter than ours.
Interestingly, our study described a D/L-treated patient who presented with virological failure following resistance development to two families of drugs: nucleoside reverse transcriptase inhibitors and integrase inhibitors. Virological failure in D/L-treated patients who develop resistance has been previously described and attributed to potential pharmacological interactions between treatments.Citation10 To the best of our knowledge, this is the second reported case of a D/L-treated patient with treatment resistance in a real-world setting. However, we attribute this resistance to the interruption and prolonged suboptimal adherence to the treatment regimen. Our study highlights the risk of treatment failure with resistance in patients with severe adherence problems, a serious adverse event that requires rescue therapy with limited future options.
This study has several limitations. First, this is a retrospective single-center study, making it difficult to extrapolate the results to other healthcare settings. Second, the exposure of B/F/T-treated patients to a higher number of treatments might undermine the comparability between the two groups. The strong points of this study are the substantial number of patients included (comparable to previous clinical trials), and a prolonged follow-up period offering a comprehensive overview of these two treatment options in a real-world setting.
Conclusions
Our study found that both optimization options, D/L and B/F/T were well tolerated and a high percentage of PLWH maintained an undetectable viraemia in a real-world setting. Special attention should be given to people switching to D/L in the event of suboptimal treatment adherence due to the risk of developing resistance.
Ethical approval
Hospital del Mar Ethics review board approved this project (23-10857) and the researchers followed the regulations of the declaration of Helsinki.
Consent form
Since the design was retrospective, the study team was waived from obtaining informed consent from participants.
Authors’ contributions
H.K: Participate in the design of the work; the analysis of data; and drafted the work. E.C-R: Participate in the interpretation of data and substantively revised the final document. A.G: Participate in the acquisition of the data. P.K: Participate in the analysis of the data and substantively revised the final document. J.V-G: Participate in the acquisition of the data. A.G-M: Participate in the acquisition of the data. C.C: Participate in the acquisition of the data. I. A-A: Participate in the acquisition of the data. A.M: Participate in the acquisition of the data. A.A-T: Participate in the acquisition of the data. R.G-F: Participate in the interpretation of data and substantively revised the final document. All the authors have read and approved the submitted version of the article.
Disclosure statement
H.K has received financial compensation for consulting and speaking engagements from Gilead Sciences, Janssen-Cilag, MSD, and ViiV Healthcare. R.G-F has received financial compensation for consulting and speaking engagements from Gilead Sciences, Janssen-Cilag, and ViiV Healthcare. The rest of the authors declare that they have no competing interests
Data availability statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Additional information
Funding
References
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