Efficacy and tolerability of dolutegravir and two nucleos(t)ide reverse transcriptase inhibitors in HIV-1-positive, virologically suppressed patients

We have read with interest the article by de Boer et al.[1] about the use of dolutegravir-containing antiretroviral regimens in real-life clinical practice. Despite the evidence emerged from phase III clinical trials [2], limited data support the use of dolutegravir-based regimens in highly treatment-experienced, virologically suppressed patients. Moreover, concerns about the tolerability of dolutegravir have emerged in this setting: de Boer et al.[1] have observed a 14.5% of dolutegravir discontinuation in treatment-experienced patients, largely due to adverse drug reactions. Similar tolerability concerns have been reported with lamivudine/abacavir/dolutegravir in a randomized trial [3,4], prompting the need for further investigations. We conducted a retrospective study in seven Italian centers to assess the efficacy and safety profiles of dolutegravir-based three-drug regimens in virologically suppressed individuals. Patients switching to dolutegravir and tenofovir/emtricitabine or abacavir/lamivudine were retrospectively enrolled, after study approval by local Ethics Committees and after acquiring an informed consent from each participant. Inclusion criteria were age older than 18 years and undetectable HIV-RNA at baseline. We estimated time to treatment failure (discontinuation of dolutegravir for any cause) and virological failure [two consecutive viral load (VL) > 50 copies/ml or one VL > 1000 copies/ml] by Kaplan–Meier method and analyzed predictors of treatment failure by Cox regression analysis and changes in immunological, metabolic, renal and liver functions at week 24 by Student's t-test. One hundred and seventy-three participants (71.7% men, 41.6% heterosexual, median age 51 years) started dolutegravir and tenofovir/emtricitabine (n = 66) or abacavir/lamivudine (n = 107). Characteristics of study population are summarized in Table 1. No virological failure was detected during 1090 patient-months of follow-up, despite a 19.2% prevalence of previously reported resistance mutations to the backbone employed. Treatment failure occurred in 16 (9.2%) participants with a median time to treatment failure of 81 days. The estimated probabilities of remaining on dolutegravir at weeks 24 and 48 were 93.7% [95% confidence interval (CI), 90.0–97.4%] and 81.0% (95% CI, 71.0–91.0%), respectively, without differences between nucleos(t)ide reverse transcriptase inhibitor–backbone type (log-rank = 0.944).Table 1: Demographic characteristics of study population at baseline.Causes of treatment failure were hypersensitivity reactions (2); gastrointestinal (1), liver (3), renal (1) and neurological (6) toxicities; drug interaction (1); and unspecified intolerance (2). All toxicities leading to treatment failure were classified as mild to moderate. Differences in causes of discontinuation between backbone types were NS (P = 0.225), although neurological events (headache, sleepiness and suicidal ideation) were mostly seen with abacavir/lamivudine (5). Male sex was the only factor associated with reduced treatment failure (hazard ratio vs female sex: 0.35; P = 0.038). At week 24, a decrease in mean total cholesterol (TC) and triglycerides was evident in the whole population but, after stratifying for backbone type, it was confirmed only in patients on tenofovir/emtricitabine (TC mean change: −22 mg/dl, P = 0.018; triglycerides: −29 mg/dl, P = 0.022). An increase in mean creatinine levels (+0.07 mg/dl, P < 0.001) was also detected, without differences between backbone type (P = 0.844). CD4+ cell count and liver enzymes did not change over time. Treatment guidelines for HIV management [5,6] suggest treatment optimization in virologically suppressed patients to manage drug toxicities, if virological efficacy is not hampered. Our study confirms the high virological efficacy and well tolerated metabolic profile of integrase inhibitor–containing switch regimens, as recently evidenced by Raffi et al.[7]. However, in the STRIVING study [3,4], switch to abacavir/lamivudine/dolutegravir yielded a higher discontinuation rate compared with standard treatment (4 vs 0%), with a proportion of these linked to neuropsychological events. In a real-life setting, de Boer et al.[1] have further shown that a significant proportion (66/454; 14.5%) of patients switching to dolutegravir discontinued their regimen, mainly due to adverse drug reaction (particularly neurological and gastrointestinal toxicities). In their cohort, and especially in the subgroup of patients discontinuing for neurological side effects, treatment discontinuation was more frequent in association with abacavir. In line with their observation, we observed a 9.2% dolutegravir-discontinuation rate (mainly for gastrointestinal or neuropsychological symptoms), which was higher than previously reported [8,9]. Also, we saw more discontinuation for neurological events in the abacavir/lamivudine group: even if abacavir use could not predict treatment failure, the hypothesized interaction [1] between abacavir and dolutegravir deserves further investigation. Our study shows some limitations, mainly due to its retrospective design and the limited time of follow-up. Nonetheless, the maintenance of viral suppression in a multicenter cohort of highly treatment-experienced patients with high prevalence of previous virological failure (42.8%) is encouraging. The observed adverse drug reaction leading to treatment failure should prompt a careful selection of patients for this type of optimization. Due to the increasing prescription of dolutegravir, extended follow-up studies on the safety of this drug in different antiretroviral combinations are needed. Acknowledgements I would like to thank all the investigators of the ODOACRE study group for the collaboration to complete this work, in particular S.D.G., A.D.L. and R.C. for data analysis; G.B., C.P., R.D.M., F.L. and M.V.C. for data collection and adverse events reports; A.C., G.S., S.R., A.L., A.G. and G.M. for the revision of the manuscript; and finally Tiziana Formenti, Letizia Oreni and Silvia Lamonica for contributing to data collection. Disclaimer: The views expressed in the present article represent the author's personal opinions and may not represent the official position of our institutions. This study was conducted as part of our routine work. During the study period, S.D.G. received speaker's honoraria from Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD) and ViiV Healthcare. G.S. received speaker's honoraria from Gilead, MSD and ViiV Healthcare.