In the last decade, less-drug regimens, mainly 2-drug regimens (2DRs), have been widely regarded as a plausible alternative to standard 3-drug regimens in virologically suppressed people living with HIV (PLWHIV), in particular in situations where data on preswitch resistance mutations are available.1 The rationale of 2DR strategies lies in the expected better tolerability and safety profile without sacrificing the virological efficacy.2,3 Lamivudine (3TC)-based 2DRs have been among the most studied switch strategies in latest years; clinical trials and observational studies analyzed the efficacy, safety, and tolerability of several 2DRs with 3TC and a boosted protease inhibitor.3–6 Since the introduction of second-generation integrase inhibitor (INI) dolutegravir (DTG), real-life reports emerged, describing the high efficacy and good tolerability profile of a 2DR with DTG + 3TC.7–9 Recently, the TANGO study,10 a randomized clinical trial, has been published, highlighting that a 2DR of DTG + 3TC was noninferior in maintaining virological suppression compared with a TAF-based 3-drug regimen. In a previous work,11 a reply to the authors of the TANGO study, we observed that there were nonsignificant differences between patients who met the TANGO inclusion criteria and those who did not, in our multicenter cohort, showing that the analyzed regimen could be effective and safe on an even larger scale. The goal of the present study, 5 years after switching our first treatment-experienced patients to DTG + 3TC, was to investigate the long-term efficacy and safety of DTG + 3TC in a multicenter real-life observational cohort of adult PLWHIV.
We performed a retrospective, observational study in which we enrolled treatment-experienced, virologically suppressed PLWHIV from 9 Italian clinical centers.12 Criteria for eligibility were patient's informed consent to data collection, being at least 18 year old, being on stable (ie, at least 6 months) antiretroviral therapy (ARV) with viral suppression (HIV-RNA<50 copies/mL) at the moment of switch to lamivudine plus dolutegravir (baseline), and being HBsAg negative.
The primary study objective was to evaluate time to virological failure (VF, defined by a single HIV-1 RNA ≥1000 copies/mL or by 2 consecutive HIV-1 RNA ≥ 50 copies/mL) and the time to treatment discontinuation (TD, defined as the interruption of either 3TC or DTG) for any cause. Survival analysis was used to determine the time to VF and TD, and the respective predictors were analyzed by Cox regression. The study was performed according to the principles of the Declaration of Helsinki and received the approval by each independent local ethics committee (study coordination site protocol number 5284/15). Data were analyzed by using SPSS Statistics for Windows, Version 23.0 (IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp).
We analyzed 785 patients: 554 were men (70.6%), with a median age of 52 years [interquartile range (IQR) 45–58 years], a median time from HIV diagnosis of 14.8 years (IQR 8.0–22.0 years), and a median time of ARV exposure of 11.5 years (IQR 5.8–18.6 years). One hundred thirty-two patients (16.8%) had at least 1 previous AIDS-defining event, and 175 (22.3%) experienced at least 1 VF, whereas 282 (35.9%) were previously prescribed a 2DR. Thirty-three (4.2%) had a previously detected M184V resistance mutation. Complete patients' characteristics are shown in Table 1.
TABLE 1. -
Patients' Characteristics at Baseline (N 785)
|Age (yr), median (IQR)
|Female, n (%)
|Risk factor for HIV infection, n (%):
|Anti-HCV antibodies positive, n (%)
|Time from HIV diagnosis (yr), median (IQR)
|CDC stage C, n (%)
|Time on antiretroviral therapy (yr), median (IQR)
|Nadir of CD4+ (cell/µL), median (IQR)
|Zenith HIV-RNA (log copies/mL), median (IQR)
|Zenith HIV-RNA > 500.000 copies/mL, n (%)
|Previous virological failure, n (%)
|CD4+ count (cell/µL), median (IQR)
|Time of virological suppression (mo), median (IQR)
|M184V resistance mutation, n (%)
|Previous HAART regimen, n (%):
| 2NRTIs + NNRTI
| 2NRTIs + PI or b/PI
| 2NRTIs + INI
| Dual therapy
|HIV subtype B, n (%)
|FTC/TDF in previous regimen, n (%)
|DTG in previous regimen, n (%)
|3TC + PI in previous regime, n (%)
|Reasons for switch, n (%):
| Gastrointestinal or liver toxicity
| Renal toxicity
| Neurological toxicity
| Other toxicities
| Drug–drug interactions
| Cardiovascular risk
| Other/unknown reasons
DTG, dolutegravir; FTC, emtricitabine; INI, inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; TDF, tenofovir disoproxil fumarate.
During 1992.6 Patient-Years of Follow-Up (PYFU), we observed 18 VF, with a rate of 0.9 VF per 100 PYFU. The median time to VF was 25.8 months (IQR 14.1–47.4 months); 10 VF (55.5%) occurred in the first 48 weeks of follow-up. Nine of the18 patients experiencing a VF discontinued study regimen, wherease the others maintained DTG + 3TC: all the patients experiencing VF reachieved virologic control subsequently. Moreover, none of the patients experiencing VF developed resistance mutation to either nucleoside reverse transcriptase inhibitors or INIs after failure, including patients with a previously detected M184V mutation. The estimated probability of maintaining virological suppression was 98.5% (SD ± 0.5) at 48 weeks, 97.7% (SD ± 0.6) at 96 weeks, 96.9% (SD ± 0.8) at 144 weeks, and 96.4% (SD ± 0.9) at 240 weeks. In a multivariate regression analysis, a non-B HIV subtype (vs subtype B, aHR 31.5, 95% CI: 2.0 to 488.9, P = 0.014) and a previous VF (aHR 24.0, 95% CI: 1.2 to 475.7, P = 0.037) resulted predictors of VF, after adjusting for nadir CD4+ cell count and peak HIV-RNA.
In appropriate survival analyses, we observed a higher probability of VF in PLWHIV with a peak HIV-RNA >500.000 copies/mL compared with others (log-rank P = 0.002), in PLWHIV with a previous VF compared with those who had never experienced a VF (log-rank P = 0.031), and in PLWHIV with a HIV subtype non-B compared with those with a subtype B (log-rank P = 0.014) Fig. 1). We did not observe differences in probability of VF in PLWHIV with a M184V resistance mutation (log-rank P = 0.689); however, in a dedicated analysis, in patients with time of virological suppression < 88 months, the M184V mutation was a predictor of VF (aHR 11.62, 95% CI: 1.15 to 117.57, P = 0.038).
During 2014.7 PYFU, we censored 150 TD, with a rate of 7.5 TD per 100 PYFU. The median time to TD was 28.6 months (IQR 14.3–47.6 months). The estimated probability of maintaining study regimen was 89.0% (SD ± 1.1) at 48 weeks, 82.9% (SD ± 1.4) at 96 weeks, 79.7% (SD ± 1.6) at 144 weeks, and 74.3% (SD ± 2.2) at 240 weeks. In our cohort, the main reasons for TD were toxicity in 54 (6.9% of total population) cases (21 for neuropsychiatric events, 11 for GI toxicity, 9 for renal toxicity, and 13 for other/unspecified toxicity), simplification to STR in 13 (1.7%) cases, weight gain in 8 cases (1.0%), death (unrelated to HIV/AIDS) in 6 cases (0.8%), VF in 9 cases (1.1%), and other/unknown in 60 cases (7.6%).
In a specific subanalysis, probability of TD after neuropsychiatric events was 9.6% at week 48 and 13.3% at weeks 96 and 144; HCV coinfection resulted the sole predictor (aHR 3.90, 95% CI: 1.05 to 14.52, P = 0.043). Among the 21 discontinuations caused by neuropsychological events, 9 were due to insomnia, 6 to headache, 5 to mood disorders, and 1 was due to the sudden onset of nightmares.
As far as immunological parameters, we observed a significant increase in CD4+ cell count at 48 weeks (median +27 cell/mm3, P < 0.001), 96 weeks (median +30 cell/mm3, P = 0.001) and 144 weeks (median +11 cell/mm3, P = 0.038). A median increase of +49 cell/mm3 was observed after 240 weeks, although it resulted nonsignificant (P = 0.073).
In our multicenter cohort of virologically suppressed PLWHIV switched to DTG + 3TC, we were able to assess the efficacy, safety, and overall tolerability of this 2DR in the long period. It has been been over 5 years that DTG + 3TC has been introduced in clinical practice as a feasible switch strategy, and results from this study appear in line with the results from clinical trials10 and other observational studies, including previous results from our cohort.8,9 Compared with patients enrolled in the TANGO study, our cohort is composed of older patients, with a longer history of HIV and ARV, and over one-fifth of the analyzed patients have experienced at least 1 VF; these differences further reinforces the strength of this combination in the real-life setting.
In this work, we observed a low VF rate (0.9 VF per 100 PYFU), with no patient experiencing the emergence of resistance mutation at failure, reflecting the safety and high genetic barrier of dolutegravir. Moreover, confirming previous findings,13 we did not observe an overall increase in the VF rate in patients with the M184V resistance mutation, but those with a reduced time of virological suppression at baseline showed an increased risk of VF in the presence of M184V.
In patients discontinuing study regimen, toxicity remained the leading cause of treatment interruption,8 with most events being of neuropsychological nature. The previously observed correlation between neuropsychiatric disorders and HCV coinfections was confirmed.8,14
Our study has some limitations, such as its retrospective nature, the lack of a control group, and the lack of recording of data on patients' compliance or minor adverse events not leading to TD. Other limitations are the low number of patients with available information regarding previous M184V mutation and the wide confidence intervals for some of the findings. However, the study also presents several strengths, including its long follow-up time, its sample size, and the real-life setting.
In conclusion, DTG+3TC confirmed its efficacy in maintaining virological suppression in a large proportion of PLWHIV in a real-life setting; clinicians should always consider patients' clinical and viro-immunological history when considering the switch to a dual regimen.
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