Short Communication: Comparing Lamivudine+Dolutegravir and Bictegravir/Emtricitabine/Tenofovir Alafenamide as Switch Strategies: Preliminary Results from Clinical Practice

Abstract

We tried to investigate and compare the safety of a dual therapy (DT) with dolutegravir+lamivudine (DTG +3TC) versus bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). We performed a retrospective analysis in a cohort of virologically suppressed HIV+ pts switching to DT or BIC in our center. Primary endpoint was to evaluate time to treatment discontinuation (TD) for any cause. Survival analysis was employed to determine time to TD and its predictors were analyzed by Cox regression. Moreover, we collected viro-immunological parameters as well as markers of renal function and lipid profile at baseline and after 24 weeks and assessed changes through nonparametric tests. We analyzed 476 patients: 350 starting a DT and 126 starting BIC. Overall, we registered 21 TD: 15 in the DT group during 170 patient-years of follow-up (PYFU) (a rate of 8.8 per 100 PYFU) and 6 in the BIC one during 48 PYFU (12.5 per 100 PYFU). Estimated probabilities of maintaining study regimen after 24 weeks were 95.5% [standard deviation (SD) ±1.1] in the DT group and 94.9% (SD ±2.0) in the BIC group, with no significant differences between them (log-rank p = .639). Concerning metabolic profile, in the DT group, after 24 weeks, triglycerides decreased significantly (median change −14 mg/dL, p < .001), whereas high-density lipoprotein cholesterol increased (+3 mg/dL, p = .031). In the BIC group, meanwhile, we observed a significant decrease in low-density lipoprotein cholesterol after 24 weeks (−13 mg/dL, p = .026). Both optimization strategies showed high tolerability in the short term in experienced pts, with few differences between them. Further studies are needed to properly assess the matter.

Background

Quality of life in people living with HIV (PLWHIV) has been markedly improved by the introduction of new antiretroviral agents that combine high virological efficacy and a good tolerability profile.¹ In particular, integrase inhibitors (INI) have become the reference pharmacological class both in treatment-naive and in experienced patients. Among INI-based switch regimens, the dual therapy (DT) with dolutegravir (DTG) and lamivudine (3TC) has been largely described in clinical trial² and observational studies^3,4 as a safe alternative to standard three-drug regimens. Studies, among other things, have highlighted its favorable metabolic profile in the medium-long term.^3,5 Recently, bictegravir (BIC), a novel INI, has been marketed as part of a single tablet regimen along with emtricitabine (FTC) and tenofovir alafenamide (TAF); phase three clinical trials have shown a neutral effect of BIC on lipid profile.^6,7 However, real-life data are still lacking. In our study, we tried to investigate and compare the safety of DTG +3TC versus BIC/FTC/TAF.

Materials and Methods

We performed a retrospective analysis in a cohort of virologically suppressed PLWHIV switching to a dual regimen with DTG +3TC (DTG group) or to a three-drug regimen with BIC (BIC group) in our clinical center. Primary endpoint was to evaluate time to treatment discontinuation (TD) for any cause. Kaplan–Meier survival analysis was employed to determine time to TD and its predictors were analyzed by Cox regression. Moreover, we collected viro-immunological parameters as well as markers of renal function and lipid profile at baseline and after 24 weeks and assessed changes through parametric and nonparametric tests, as appropriate. Predictors of changes were analyzed by linear regression.

The study was approved by the local Ethics Committee (protocol number: 5284/15) and all patients signed informed consent for data collection.

Results

We analyzed 476 patients: 350 were included in the DTG group and 126 in the BIC one. In our cohort, 336 patients (70.0%) were males, median age was 53 years [interquartile range (IQR) 44–58] with a median time from HIV diagnosis of 15 years (IQR 7–22). At baseline, median CD4+ cell count was 650 cell/mm³ (IQR 500–874). Patients in the BIC group were more frequently coinfected with HCV and had a shorter median time of virological suppression compared with those in DT. Moreover, patients in the BIC group switched mainly for treatment simplification and more frequently from a three-drug regimen with a backbone of two nucleoside reverse transcriptase inhibitors (NRTIs) and an INI. Full baseline characteristics and differences between groups are summarized in Table 1.

Table 1.

Patients' Characteristics at Baseline

Variable	DTG (n = 354)	BIC (n = 126)	p
Male sex, n (%)	246 (69.5)	90 (71.4)	ns
Age, median (IQR)	52.4 (43.4–58.5)	53.1 (43.7–58.3)	ns
HIV risk factor, n (%)			.021
Heterosexual	150 (42.4)	48 (38.1)
MSM	150 (42.4)	44 (34.9)
IDU	34 (9.6)	25 (19.8)
Other/unknown	20 (5.7)	9 (7.2)
HCV-coinfected, n (%)	40 (11.7)	24 (19.5)	.030
Years from HIV diagnosis, median (IQR)	14.2 (7.2–20.3)	17.3 (5.1–24.2)	ns
CDC stage C, n (%)	109 (30.8)	40 (31.7)	ns
Years of ART, median (IQR)	11.6 (5.4–18.5)	12.7 (4.6–21.0)	ns
Years of virological suppression, median (IQR)	7.9 (3.5–11.7)	5.0 (2.4–10.9)	.024
CD4+ cell nadir, median (IQR)	202 (68–308)	180 (64–337)	ns
Zenith HIV-RNA (log10 copies/mL), median (IQR)	4.83 (4.14–5.36)	4.92 (4.23–5.51)	ns
Previous ART regimen			<.001
2NRTI+PI	66 (18.6)	13 (10.3)
2NRTI+NNRTI	23 (6.5)	4 (3.2)
2NRTI+INI	120 (33.9)	101 (80.2)
Dual	139 (39.3)	8 (6.3)
Other	6 (1.7)	0
Dual 3TC-based	121 (34.3)	8 (6.3)	<.001
Reason for switch			<.001
Simplification	181 (51.1)	114 (90.5)
Dyslipidemia	71 (20.1)	0
Toxicity	70 (19.8)	4 (3.2)
DDI	12 (3.4)	2 (1.6)
Other/unknown	20 (5.6)	6 (4.8)
Comorbidities at baseline			ns
Hypertension	50 (14.1)	11 (8.7)
Diabetes	9 (2.5)	2 (1.6)
Chronic heart disease	49 (13.8)	12 (9.5)

3TC, lamivudine; ART, antiretroviral therapy; CDC, Center for Disease Control; DDI, drug-drug interaction; DTG, dolutegravir; HCV, hepatitis C virus; IDU, intravenous drug user; INI, integrase inhibitors; IQR, interquartile range; MSM, men who have sex with men; NRTI, nucleoside reverse transcriptase inhibitors; ns, not significant; PI, protease inhibitor.

Overall, we registered 21 TD: 15 in the DTG group during 170 patient-years of follow-up (PYFU) (a rate of 8.8 per 100 PYFU) and 6 in the BIC one during 48 PYFU (12.5 per 100 PYFU). Reasons for TD in the DT group were gastrointestinal (GI) toxicity in five cases (1.4% of the group), neuropsychiatric events in three cases (0.8%; one case of headache, one of depression, and one of incubi), other toxicity in four cases (1.1%) and other/unknown reasons in three cases (0.9%); in the BIC group reasons for TD were GI toxicity in two cases (1.6%), neuropsychiatric events in two cases (one case of insomnia and one of vertigo) and other/unknown reasons in other two cases. Estimated probability of maintaining study regimen after 24 weeks was 95.5% [standard deviation (SD) ±1.1] in the DTG group and 94.9% (SD ±2.0) in the BIC group, with no significant differences between them (log-rank p = .639). No predictor of TD was found in our cohort. In a dedicated subanalysis, we found no differences in the estimated probability of discontinuing study regimen for central nervous system toxicity at 24 weeks between the DTG and BIC groups (98.3% vs. 94.5%, respectively, p = .742).

Concerning metabolic profile, in the DTG group, after 24 weeks, triglycerides decreased significantly (median change −14 mg/dL, p < .001), whereas high-density lipoprotein (HDL) cholesterol increased (+3 mg/dL, p = .031). Changes in triglycerides levels were reversely associated with baseline values (per 10 mg/dL more, B − 9.6, 95% CI −10.6 to −8.7, p < .001); similarly, the increase in HDL was solely predicted by baseline HDL values (per 10 mg/dL more, B − 7.6, 95% CI −9.3 to −5.9, p < .001). In the BIC group, meanwhile, we observed a significant decrease in low-density lipoprotein (LDL) cholesterol after 24 weeks (−13 mg/dL, p = .026); such decrease was predicted by baseline LDL value (per 10 mg/dL more, B − 9.9, 95% CI −11.6 to −8.2, p < .001). Patients in the BIC group also presented a decrease in triglycerides, although nonsignificant (−9.1 mg/dL, p = .121). As to renal function, patients in the DTG group saw their estimated glomerular filtration rate (eGFR) decrease (−8.36 mL/min, p < .001). The decrease of eGFR was worse in patients with a higher baseline eGFR (per 10 mL/min more, −8.6, 95% CI −10.1 to −7.1, p < .001). No significant variations were observed in the BIC group. However, eGFR changes between groups were not significant (p = .190).

In a dedicated subanalysis, patients >60 years showed a significant reduction in total cholesterol level in the DTG group (−17 mg/dL, p = .005), whereas such reduction was not observed in the BIC group (p = .311). In a multivariate analysis, baseline total cholesterol resulted the sole predictor of such variation (per 10 mg/dL more, B − 7.6, 95% CI −10.4 to −4.8, p < .001).

Considering only the women in our cohort, we observed a significant decrease in total cholesterol both in the DTG group (−11.8 mg/dL, p = .040) and in the BIC group (−29.5 mg/dL, p = .027). In the BIC group, the decrease was independent from baseline cholesterol value (p = .115); in the DTG group, meanwhile, baseline cholesterol resulted the only predictor of the decrease (per 10 mg/dL more, B − 10.9, 95% CI −13.2 to −8.7, p < .001). Women in the DTG group also showed a significant decrease of eGFR after 24 weeks (−10.2 mL/min, p = .024), not observed in women in the BIC group (p = .925).

Discussion

In our study enrolling virologically suppressed PLWHIV, both DTG +3TC and FTC/TAF/BIC showed high tolerability, with a low rate of overall TDs. Main reason for TD was toxicity (mainly regarding the GI tract) in both groups, with no difference in probability of TD after 24 weeks between the groups. Given the high incidence of DTG discontinuations after neuropsychiatric events reported in some studies, we performed dedicated subanalyses, failing to find differences between the two groups in probability of INI discontinuations for this reason. These results are in line with previous findings from Hoffman et al. ⁸

Although the study was not designed to assess differences in virological efficacy, it is to be noted that no virological failures (defined as two consecutive HIV-RNA determinations >50 copies/mL or a single determination >1,000 copies/mL) were observed in our cohort.

Regarding the metabolic profile, both strategies showed a favorable effect on cholesterol and triglycerides. This finding is of particular interest, since reports have emerged reporting a worsening in lipid profile after switching to TAF^9,10; this was expected since TAF does not share the same “statin-like” effect that TDF has, although its clinical impact remains controversial. In our study, patients on BIC/FTC/TAF presented a significant decrease in LDL cholesterol and a slight nonsignificant decrease in triglycerides; moreover, such variation was not influenced by the preswitch regimen (i.e., switching from a TDF-based regimen).

The decrease in total cholesterol levels, meanwhile, was particularly pronounced in women (for both groups) and in elderly patients (in the DTG group). Patients in the DTG group also experienced a decrease in eGFR, a feature already described in the literature,³ likely due to the fact that DTG inhibits the organic cation transporter 2 (OCT2), thus reducing the excretion at the tubular level of creatinine.¹¹ Such finding was not observed in patients in the BIC group.

Our study presents obvious limitations such as its retrospective nature and the short follow-up time. Further studies are needed to properly assess the matter. Moreover, it is worth mentioning that reasons for starting DT and BIC were widely different, with a large proportion of patients starting DT because of dyslipidemia, whereas no patient switched to BIC for such reason. This must be taken into account when considering the observed changes in lipid profile. However, to the best of our knowledge, this is the first work comparing FTC/TAF/BIC with the dual regimen of DTG +3TC, allowing a first comparison between two of the most promising switch strategies on the market today.

In conclusion, in our study we found that both optimization strategies showed high tolerability in the short term in experienced PLWHIV, with few differences between them.

Footnotes

Authors' Contributions

G.B., A.C., A.B., and S.D.G. contributed to the conception and design of the study. G.B. and A.C. contributed to the draft of the article. A.D.A., A.D., A.E., D.M., C.P., and D.F. contributed to the acquisition of the data. G.B., A.C., and F.L. contributed to the analysis and interpretation of data. G.B., A.C., A.B., and S.D.G. contributed to the critical revision of the article for important intellectual content. All authors approved the final version of the article.

Author Disclosure Statement

A.C. has received travel grants from ViiV Healthcare. A.B. has received nonfinancial support from Bristol-Myers Squibb and ViiV Healthcare, and personal fees from Gilead Sciences and Janssen. S.D.G. was a paid consultant or member of advisory boards for Gilead, ViiV Healthcare, Janssen-Cilag, Merck Sharp & Dohme and Bristol-Myers Squibb. All other authors have none to declare.

Funding Information

This study was performed as part of our routine work.

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