Dolutegravir Plus Lamivudine as a Switch Strategy

Results

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.

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) Figure 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).

(Enlarge Image)

Figure 1.

Kaplan–Meier survival analyses. A, Stratified for Zenith HIV-RNA; (B) stratified for previous virological failures; (C) stratified for the presence of the M184V mutation; and (D) stratified for HIV subtype.

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).

Table 1. Patients' Characteristics at Baseline (N 785)
Variables
Age (yr), median (IQR)	52.3 (44.9–58.2)
Female, n (%)	231 (29.4)
Risk factor for HIV infection, n (%):
Heterosexual	319 (40.6)
MSM	305 (38.9)
IDU	119 (15.2)
Others	42 (5.3)
Anti-HCV antibodies positive, n (%)	64 (8.2)
Time from HIV diagnosis (yr), median (IQR)	14.9 (8.0–22.0)
CDC stage C, n (%)	132 (16.8)
Time on antiretroviral therapy (yr), median (IQR)	11.5 (5.9–18.6)
Nadir of CD4⁺ (cell/μL), median (IQR)	225 (96–331)
Zenith HIV-RNA (log copies/mL), median (IQR)	4.94 (4.39–5.45)
Zenith HIV-RNA > 500.000 copies/mL, n (%)	110 (14.0)
Previous virological failure, n (%)	175 (22.3)
CD4⁺ count (cell/μL), median (IQR)	680 (500–889)
Time of virological suppression (mo), median (IQR)	29.1 (14.6–49.5)
M184V resistance mutation, n (%)
Present	33 (4.2)
Absent	214 (27.3)
Unknown	538 (68.5)
Previous HAART regimen, n (%):
2NRTIs + NNRTI	180 (22.9)
2NRTIs + PI or b/PI	92 (11.7)
2NRTIs + INI	216 (27.5)
Dual therapy	268 (34.1)
Other	29 (3.7)
HIV subtype B, n (%)	91 (11.6)
FTC/TDF in previous regimen, n (%)	253 (32.3)
DTG in previous regimen, n (%)	147 (18.7)
3TC + PI in previous regime, n (%)	216 (27.5)
Reasons for switch, n (%):
Simplification	302 (38.5)
Dyslipidemia	96 (12.2)
Gastrointestinal or liver toxicity	49 (6.2)
Renal toxicity	32 (4.1)
Osteoporosis	27 (3.4)
Neurological toxicity	6 (0.8)
Other toxicities	28 (3.6)
Drug–drug interactions	50 (6.4)
Cardiovascular risk	21 (2.7)
Other/unknown reasons	174 (22.2)

Table 1. Patients' Characteristics at Baseline (N 785)

Variables

Age (yr), median (IQR)

52.3 (44.9–58.2)

Female, n (%)

231 (29.4)

Risk factor for HIV infection, n (%):

Heterosexual

319 (40.6)

MSM

305 (38.9)

IDU

119 (15.2)

Others

42 (5.3)

Anti-HCV antibodies positive, n (%)

64 (8.2)

Time from HIV diagnosis (yr), median (IQR)

14.9 (8.0–22.0)

CDC stage C, n (%)

132 (16.8)

Time on antiretroviral therapy (yr), median (IQR)

11.5 (5.9–18.6)

Nadir of CD4⁺ (cell/μL), median (IQR)

225 (96–331)

Zenith HIV-RNA (log copies/mL), median (IQR)

4.94 (4.39–5.45)

Zenith HIV-RNA > 500.000 copies/mL, n (%)

110 (14.0)

Previous virological failure, n (%)

175 (22.3)

CD4⁺ count (cell/μL), median (IQR)

680 (500–889)

Time of virological suppression (mo), median (IQR)

29.1 (14.6–49.5)

M184V resistance mutation, n (%)

Present

33 (4.2)

Absent

214 (27.3)

Unknown

538 (68.5)

Previous HAART regimen, n (%):

2NRTIs + NNRTI

180 (22.9)

2NRTIs + PI or b/PI

92 (11.7)

2NRTIs + INI

216 (27.5)

Dual therapy

268 (34.1)

Other

29 (3.7)

HIV subtype B, n (%)

91 (11.6)

FTC/TDF in previous regimen, n (%)

253 (32.3)

DTG in previous regimen, n (%)

147 (18.7)

3TC + PI in previous regime, n (%)

216 (27.5)

Reasons for switch, n (%):

Simplification

302 (38.5)

Dyslipidemia

96 (12.2)

Gastrointestinal or liver toxicity

49 (6.2)

Renal toxicity

32 (4.1)

Osteoporosis

27 (3.4)

Neurological toxicity

6 (0.8)

Other toxicities

28 (3.6)

Drug–drug interactions

50 (6.4)

Cardiovascular risk

21 (2.7)

Other/unknown reasons

174 (22.2)

Authors and Disclosures

Arturo Ciccullo, MD^a,b, Vanni Borghi, MD^c, Andrea Giacomelli, MD^d, Maria Vittoria Cossu, MD^e, Gaetana Sterrantino, MD^f, Alessandra Latini, MD^g, Andrea Giacometti, MD^h, Andrea De Vito, MDⁱ, William Gennari, MD^j, Giordano Madeddu, MDⁱ, Amedeo Capetti, MD^e, Gabriella d'Ettorre, MD^k, Cristina Mussini, MD^c, Stefano Rusconi, MD^d, Simona Di Giambenedetto, MD^b,l and Gianmaria Baldin, MD^l,m

^aUOC Malattie Infettive, P.O. San Salvatore, L'Aquila, Italy; ^bCatholic University of the Sacred Heart, Rome, Italy; ^cAzienda Ospedaliero Universitaria di Modena, Clinica Malattie Infettive e Tropicali, Modena, Italy; ^dInfectious Diseases Unit, DIBIC Luigi Sacco, University of Milan, Milan, Italy; ^eDivision of Infectious Diseases, Department of Infectious Diseases, Luigi Sacco University Hospital, Milan, Italy; ^fInfectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy; ^gInfectious Dermatology and Allergology Unit, IFO S. Gallicano Institute (IRCCS), Rome, Italy; ^hClinic of Infectious Diseases, Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona. Italy; ⁱUnit of Infectious Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; ^jAzienda Ospedaliero Universitaria di Modena Laboratorio di Microbiologia e Virologia, Modena, Italy; ^kDepartment of Public Health and Infectious Diseases, Azienda Policlinico Umberto I, Rome, Italy; ^lUOC Malattie Infettive, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; and ^mMater Olbia Hospital, Olbia, Italy.

Correspondence to
Arturo. Ciccullo, MD, UOC Malattie Infettive, P.O. San Salvatore, via Lorenzo Natali 1, L'Aquila (AQ) 67100, Italy (e-mail: arturo.ciccullo@gmail.com).

A. Ciccullo received travel grants from ViiV Healthcare. A.G. reports grants and/or personal fees from BMS, Gliead, Janssen, MSD and ViiV Healthcare. A. Capetti has received a personal grant from AB, Gilead, and ViiV. G.S. has received funds for speaking by Gilead, Merck, Janssen, AbbVie, and ViiV. C.M. has participated in advisory boards and received study grants and/or speaker honoraria from AbbVie, Gilead, ViiV, Janssen, Angelini, BMS, and MSD. S.R. received research grants to his institution from ViiV Heathcare, Gilead Sciences, and Janssen, outside the submitted work; he was also a paid consultant for ViiV Heathcare, Gilead Sciences, Merck Sharp & Dohme, Bristol-Myers Squibb, 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. The remainig authors have no conflicts of interest to disclose.