Atazanavir/ritonavir with lamivudine as maintenance therapy in virologically suppressed HIV-infected patients: 96 week outcomes of a randomized trial

Atazanavir/ritonavir with lamivudine as maintenance therapy in virologically suppressed... Abstract Objectives To investigate the long-term safety and efficacy of a treatment switch to dual ART with atazanavir/ritonavir + lamivudine versus continuing a standard regimen with atazanavir/ritonavir + 2NRTI in virologically suppressed patients. Methods ATLAS-M is a 96 week open-label, randomized, non-inferiority (margin −12%) trial enrolling HIV-infected adults on atazanavir/ritonavir + 2NRTI, with stable HIV-RNA <50 copies/mL and CD4 counts >200 cells/mm3. At baseline, patients were randomized 1:1 to switch to atazanavir/ritonavir + lamivudine or to continue the previous regimen. Here, we report the 96 week efficacy and safety data. The study was registered with ClinicalTrials.gov, number NCT01599364. Results Overall, 266 subjects were enrolled (133 in each arm). At 96 weeks, in the ITT population, patients free of treatment failure totalled 103 (77.4%) with atazanavir/ritonavir + lamivudine and 87 (65.4%) with triple therapy (difference +12.0%, 95% CI +1.2/+22.8, P = 0.030), demonstrating the superiority of dual therapy. Two (1.5%) and 9 (6.8%) virological failures occurred in the dual-therapy arm and the triple-therapy arm, respectively, without development of resistance to any study drug. Clinical adverse events occurred at similar rates in both arms. A higher frequency of grade 3–4 hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) occurred with dual therapy, although this never led to treatment discontinuation. A significant improvement in renal function and lumbar spine bone mineral density occurred in the dual-therapy arm. The evolution of CD4, HIV-DNA levels and neurocognitive performance was similar in both arms. Conclusions In this randomized study, a treatment switch to atazanavir/ritonavir + lamivudine was superior over the continuation of atazanavir/ritonavir + 2NRTI in virologically suppressed patients, with a sustained benefit in terms of improved renal function and bone mineral density. Introduction In recent years, drug reduction strategies to mono/dual therapies in HIV-infected patients have been investigated in order to improve long-term ART tolerability and to reduce costs while maintaining virological efficacy.1–3 Dual therapies combining a boosted PI with lamivudine have been the most intensively investigated treatments, both in naive and in virologically suppressed patients.4–13 The combination of atazanavir/ritonavir + lamivudine has shown promising results in virologically suppressed patients: two randomized studies, SALT and ATLAS-M, demonstrated non-inferior efficacy of a treatment switch to atazanavir/ritonavir + lamivudine when compared with a standard atazanavir/ritonavir-based triple therapy after a 48 week follow-up.8,9 In ATLAS-M, atazanavir/ritonavir + lamivudine even showed superior efficacy over the comparator arm at the primary study endpoint and a benefit in terms of evolution of renal function.8 It is important to investigate whether these favourable results obtained at 48 weeks persist at longer durations. The 96 week data of SALT trial have confirmed the long-term non-inferior efficacy of treatment simplification to atazanavir/ritonavir + lamivudine with no significant benefit in terms of tolerability over triple therapy.10 Here, we report the final 96 week efficacy and safety data of the ATLAS-M trial, investigating treatment simplification to atazanavir/ritonavir + lamivudine versus continuing the baseline regimen in patients who are virologically suppressed under an atazanavir/ritonavir-based triple therapy. We also report results of patients’ neurocognitive performance, bone mineral density and body fat distribution changes as well as the evolution of peripheral blood HIV-1-DNA levels at 96 weeks in the two study arms. Methods Study design, patients and procedures The design of the ATLAS-M trial has been reported elsewhere.8 Briefly, ATLAS-M is a 96 week open-label, randomized, non-inferiority trial comparing a treatment switch to 300 mg of atazanavir boosted with 100 mg of ritonavir once daily plus 300 mg of lamivudine once daily (atazanavir/ritonavir + lamivudine arm) with continuation of a standard triple-therapy regimen with 300 mg of atazanavir boosted with 100 mg of ritonavir once daily plus two NRTIs (atazanavir/ritonavir + 2NRTI arm) in virologically suppressed patients. Adult (>18 years old), HIV-1-infected patients on an antiretroviral regimen including atazanavir/ritonavir + 2NRTI from at least 3 months, with HIV-RNA <50 copies/mL and CD4 >200 cells/mm3 from at least 6 months, no previous virological failure on or resistance to atazanavir and/or lamivudine, no previous exposure to mono/dual therapies and no HBV coinfection were randomized 1:1 at baseline to atazanavir/ritonavir + lamivudine (study arm) or to continue the standard triple therapy (atazanavir/ritonavir + 2NRTI arm). The study was powered to demonstrate non-inferior efficacy with a lower margin of 12% of the study regimen versus the control arm at the primary study outcome: absence of treatment failure at 48 weeks in the ITT exposed population.8 Follow-up study visits were planned at weeks 4 and 12 and then every 12 weeks until week 96, monitoring physical examination, routine laboratory tests (HIV-RNA, CD4 count, blood chemistry, urinalysis) and treatment adherence (on a 0–100 visual analogue scale).14 At baseline, week 48 and week 96, whole body, lumbar and hip dual-energy X-ray absorptiometry (DEXA) scans was performed in a subgroup of patients. Bone metabolism biomarkers (25-OH vitamin D, parathyroid hormone, osteocalcin, calcitonin, bone alkaline phosphatase) were also assessed at the same timepoints. Osteopenia and osteoporosis were defined according to standard criteria.15 Body fat distribution was assessed by measuring total, limb and trunk fat/lean mass. Moreover, a comprehensive neuropsychological examination was also performed at baseline, week 48 and week 96. Exclusion criteria for this substudy were: active psychiatric disorders/alcoholism or drug abuse, and linguistic difficulties for non-native patients. The following cognitive domains were investigated: Verbal Learning (Immediate and Delayed Recall of Rey’s words), Attention and Working Memory (WAIS digit span and WAIS digit symbol), Language (Fluency test), and Fine Motor Skills (Grooved Pegboard Test). Individual scores on each cognitive test were transformed into Z scores and averaged to calculate a composite domain-specific Z score; cognitive impairment was defined according to Frascati criteria.16 Total HIV-DNA was quantified in whole blood at baseline, and after 48 and 96 weeks, using a TaqMan real-time PCR technique, as previously described.17 This assay takes both integrated and non-integrated HIV-DNA forms into account. Results were expressed as the log10-transformed HIV-DNA copies/106 leucocytes to normalize the distribution. Treatment failure was defined by any of the following: virological failure, any treatment modification or discontinuation, loss to follow-up, consent withdrawal, progression to AIDS, or death from any cause. Virological failure was defined as the first of two consecutive HIV-RNA levels >50 copies/mL or a single level >1000 copies/mL. Viral blips were defined as a transient HIV-RNA level >50 copies/mL preceded and followed by viral loads <50 copies/mL without any treatment change. Genotypic resistance testing and measurement of atazanavir plasma levels through a validated HPLC method18 were performed on plasma samples at the time of virological failure. The evaluation of the proportion of patients without treatment failure at week 96 was a secondary study endpoint. Analysis of the efficacy endpoint was performed both on the ITT exposed (ITT-e) population and the PP population. In addition, FDA snapshot analyses of treatment efficacy (success = any patient in study with an HIV-RNA <50 copies/mL in the time window ± 4 weeks) were carried out at 96 weeks in both the ITT-e and PP populations. The non-inferiority margin for the comparison of atazanavir/ritonavir + lamivudine versus atazanavir/ritonavir + 2NRTI was set at −12%. Superiority was assessed post hoc. Other secondary endpoints included the development of virological failure and drug resistance, occurrence of clinical and laboratory adverse events, changes in CD4 cell count, HIV-DNA, blood lipid levels and renal function, and self-reported adherence from baseline to week 96. Ethics The protocol was approved by the Ethics Committees of each participating centre and all procedures were performed in accordance with the Declaration of Helsinki. Patients provided written informed consent to study participation before enrolment. The study was registered with ClinicalTrials.gov, number NCT01599364. Statistical analysis Descriptive statistics were used to describe the baseline characteristics of patients. Categorical variables were compared using the χ2 test or Fisher’s exact test, as appropriate. Continuous variables were compared using the Student’s t-test or the Mann–Whitney U-test if they were normally or non-normally distributed, respectively. Only P values ≤0.05 were considered to be significant. All analyses were performed using the SPSS version 18.0 software package (SPSS Inc., Chicago, IL, USA). Results Patient characteristics Overall, 275 patients were screened for study participation and 266 patients were randomized, 133 to each study arm. Patient disposition at 96 weeks is illustrated in Figure 1. Baseline patients’ characteristics have been described previously.8 Briefly, 79.7% (n = 212) of patients were male with a median age of 44 years (IQR 36–50); 10.5% (n = 28) were HCV coinfected and 12.8% (n = 34) reported a previous AIDS-defining event. At baseline, patients had HIV-RNA <50 copies/mL from a median of 22.0 months (IQR 12.6–45.0) with a median CD4 count of 617 cells/mm3 (IQR 481–781). Before baseline, the NRTI backbone included tenofovir disoproxil fumarate in the majority of patients [n = 217 (81.6%)]. At baseline, the two arms were well balanced for the main characteristics (Table 1). Table 1. Baseline patient characteristics Total population, N = 266 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 Age (years)* 44 (36–50) 44 (36–49) 44 (36–51) Male 212 (79.7) 112 (84.2) 100 (75.2) Race  Caucasian 248 (93.2) 125 (94.0) 123 (92.5)  black 12 (4.5) 5 (3.8) 7 (5.3)  Latin American 5 (1.9) 2 (1.5) 3 (2.3)  other 1 (0.4) 1 (0.8) 0 (0.0) Risk factor  heterosexual 108 (40.6) 48 (36.1) 60 (45.1)  homo/bisexual 116 (43.6) 64 (48.1) 52 (39.1)  IVDU 20 (7.5) 9 (6.8) 11 (8.3)  other/unknown 22 (8.3) 12 (9.0) 10 (7.5) HCV coinfection 28 (10.5) 14 (10.5) 14 (10.5) Previous AIDS events 34 (12.8) 18 (13.5) 16 (12.0) Years from HIV diagnosis* 4.5 (2.2–9.5) 4.2 (2.2–9.0) 5.2 (2.6–10.3) Years from first ART initiation* 2.7 (1.6–5.5) 2.8 (1.7–5.1) 2.7 (1.6–6.4) ART line* 2 (1–3) 2 (1–3) 2 (1–3) Months from last regimen initiation* 29.1 (17.1–53.0) 28.7 (17.9–52.9) 29.2 (16.2–54.6) NRTI backbone  TDF+FTC/3TC 217 (81.6) 105a (78.9) 112a (84.2)  ABC+3TC 43 (16.2) 25 (18.8) 18 (13.5)  other 6 (2.3) 3b (2.3) 3c (2.3) Nadir CD4 count (cells/mm3)* 265 (132–357) 274 (118–357) 257 (144–357) Current CD4 count (cells/mm3)* 617 (481–781) 622 (472–779) 616 (486–783) Months from last HIV-1-RNA >50 copies/mL* 22.0 (12.6–45.0) 23.5 (12.6–46.5) 20.8 (12.3–44.8) Total population, N = 266 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 Age (years)* 44 (36–50) 44 (36–49) 44 (36–51) Male 212 (79.7) 112 (84.2) 100 (75.2) Race  Caucasian 248 (93.2) 125 (94.0) 123 (92.5)  black 12 (4.5) 5 (3.8) 7 (5.3)  Latin American 5 (1.9) 2 (1.5) 3 (2.3)  other 1 (0.4) 1 (0.8) 0 (0.0) Risk factor  heterosexual 108 (40.6) 48 (36.1) 60 (45.1)  homo/bisexual 116 (43.6) 64 (48.1) 52 (39.1)  IVDU 20 (7.5) 9 (6.8) 11 (8.3)  other/unknown 22 (8.3) 12 (9.0) 10 (7.5) HCV coinfection 28 (10.5) 14 (10.5) 14 (10.5) Previous AIDS events 34 (12.8) 18 (13.5) 16 (12.0) Years from HIV diagnosis* 4.5 (2.2–9.5) 4.2 (2.2–9.0) 5.2 (2.6–10.3) Years from first ART initiation* 2.7 (1.6–5.5) 2.8 (1.7–5.1) 2.7 (1.6–6.4) ART line* 2 (1–3) 2 (1–3) 2 (1–3) Months from last regimen initiation* 29.1 (17.1–53.0) 28.7 (17.9–52.9) 29.2 (16.2–54.6) NRTI backbone  TDF+FTC/3TC 217 (81.6) 105a (78.9) 112a (84.2)  ABC+3TC 43 (16.2) 25 (18.8) 18 (13.5)  other 6 (2.3) 3b (2.3) 3c (2.3) Nadir CD4 count (cells/mm3)* 265 (132–357) 274 (118–357) 257 (144–357) Current CD4 count (cells/mm3)* 617 (481–781) 622 (472–779) 616 (486–783) Months from last HIV-1-RNA >50 copies/mL* 22.0 (12.6–45.0) 23.5 (12.6–46.5) 20.8 (12.3–44.8) ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; ABC, abacavir. Values are expressed as n (%) except for *median (IQR). a One patient in each arm treated with TDF + 3TC and all others with TDF + FTC. b Two patients treated with zidovudine + 3TC and one patient treated with didanosine + 3TC. c One patient treated with zidovudine + 3TC, one patient treated with TDF + ABC and one patient treated with no NRTI backbone (treated with atazanavir/ritonavir + raltegravir, major protocol deviation). Table 1. Baseline patient characteristics Total population, N = 266 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 Age (years)* 44 (36–50) 44 (36–49) 44 (36–51) Male 212 (79.7) 112 (84.2) 100 (75.2) Race  Caucasian 248 (93.2) 125 (94.0) 123 (92.5)  black 12 (4.5) 5 (3.8) 7 (5.3)  Latin American 5 (1.9) 2 (1.5) 3 (2.3)  other 1 (0.4) 1 (0.8) 0 (0.0) Risk factor  heterosexual 108 (40.6) 48 (36.1) 60 (45.1)  homo/bisexual 116 (43.6) 64 (48.1) 52 (39.1)  IVDU 20 (7.5) 9 (6.8) 11 (8.3)  other/unknown 22 (8.3) 12 (9.0) 10 (7.5) HCV coinfection 28 (10.5) 14 (10.5) 14 (10.5) Previous AIDS events 34 (12.8) 18 (13.5) 16 (12.0) Years from HIV diagnosis* 4.5 (2.2–9.5) 4.2 (2.2–9.0) 5.2 (2.6–10.3) Years from first ART initiation* 2.7 (1.6–5.5) 2.8 (1.7–5.1) 2.7 (1.6–6.4) ART line* 2 (1–3) 2 (1–3) 2 (1–3) Months from last regimen initiation* 29.1 (17.1–53.0) 28.7 (17.9–52.9) 29.2 (16.2–54.6) NRTI backbone  TDF+FTC/3TC 217 (81.6) 105a (78.9) 112a (84.2)  ABC+3TC 43 (16.2) 25 (18.8) 18 (13.5)  other 6 (2.3) 3b (2.3) 3c (2.3) Nadir CD4 count (cells/mm3)* 265 (132–357) 274 (118–357) 257 (144–357) Current CD4 count (cells/mm3)* 617 (481–781) 622 (472–779) 616 (486–783) Months from last HIV-1-RNA >50 copies/mL* 22.0 (12.6–45.0) 23.5 (12.6–46.5) 20.8 (12.3–44.8) Total population, N = 266 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 Age (years)* 44 (36–50) 44 (36–49) 44 (36–51) Male 212 (79.7) 112 (84.2) 100 (75.2) Race  Caucasian 248 (93.2) 125 (94.0) 123 (92.5)  black 12 (4.5) 5 (3.8) 7 (5.3)  Latin American 5 (1.9) 2 (1.5) 3 (2.3)  other 1 (0.4) 1 (0.8) 0 (0.0) Risk factor  heterosexual 108 (40.6) 48 (36.1) 60 (45.1)  homo/bisexual 116 (43.6) 64 (48.1) 52 (39.1)  IVDU 20 (7.5) 9 (6.8) 11 (8.3)  other/unknown 22 (8.3) 12 (9.0) 10 (7.5) HCV coinfection 28 (10.5) 14 (10.5) 14 (10.5) Previous AIDS events 34 (12.8) 18 (13.5) 16 (12.0) Years from HIV diagnosis* 4.5 (2.2–9.5) 4.2 (2.2–9.0) 5.2 (2.6–10.3) Years from first ART initiation* 2.7 (1.6–5.5) 2.8 (1.7–5.1) 2.7 (1.6–6.4) ART line* 2 (1–3) 2 (1–3) 2 (1–3) Months from last regimen initiation* 29.1 (17.1–53.0) 28.7 (17.9–52.9) 29.2 (16.2–54.6) NRTI backbone  TDF+FTC/3TC 217 (81.6) 105a (78.9) 112a (84.2)  ABC+3TC 43 (16.2) 25 (18.8) 18 (13.5)  other 6 (2.3) 3b (2.3) 3c (2.3) Nadir CD4 count (cells/mm3)* 265 (132–357) 274 (118–357) 257 (144–357) Current CD4 count (cells/mm3)* 617 (481–781) 622 (472–779) 616 (486–783) Months from last HIV-1-RNA >50 copies/mL* 22.0 (12.6–45.0) 23.5 (12.6–46.5) 20.8 (12.3–44.8) ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; ABC, abacavir. Values are expressed as n (%) except for *median (IQR). a One patient in each arm treated with TDF + 3TC and all others with TDF + FTC. b Two patients treated with zidovudine + 3TC and one patient treated with didanosine + 3TC. c One patient treated with zidovudine + 3TC, one patient treated with TDF + ABC and one patient treated with no NRTI backbone (treated with atazanavir/ritonavir + raltegravir, major protocol deviation). Figure 1. View largeDownload slide Flow chart showing patient allocation throughout the study and main study outcomes. ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; RAL, raltegravir. Figure 1. View largeDownload slide Flow chart showing patient allocation throughout the study and main study outcomes. ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; RAL, raltegravir. Efficacy analysis At 96 weeks, in the ITT-e population, patients free of treatment failure numbered 103/133 (77.4%, 95% CI 70.3/84.5) in the atazanavir/ritonavir + lamivudine arm and 87/133 (65.4%, 95% CI 57.3/73.5) in the atazanavir/ritonavir + 2NRTI arm (difference atazanavir/ritonavir + lamivudine minus atazanavir/ritonavir + 2NRTI +12.0%, 95% CI +1.2/+22.8, P = 0.030) (Figure 2). Figure 2. View largeDownload slide Proportion of patients without treatment failure at week 96 (bottom) and differences between the two arms (top). ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; S = F, switch equal to failure. Figure 2. View largeDownload slide Proportion of patients without treatment failure at week 96 (bottom) and differences between the two arms (top). ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; S = F, switch equal to failure. Similar results were observed in the PP population: 102/131 (77.9%, 95% CI 70.8/85.0) patients in the atazanavir/ritonavir + lamivudine arm compared with 84/129 (65.1%, 95% CI 56.9/73.3) patients in the atazanavir/ritonavir + 2NRTI arm were free of treatment failure (difference between arms +12.8%, 95% CI +1.9%/+23.7%, P = 0.023). These results fulfil the predefined non-inferiority criteria and indicate superior efficacy of switching to atazanavir/ritonavir + lamivudine over continuing atazanavir/ritonavir + 2NRTI. The 96 week snapshot analysis also confirmed the superiority of switching to atazanavir/ritonavir + lamivudine. In the ITT-e population, 103/133 patients (77.4%, 95% CI 70.3/84.5) in the atazanavir/ritonavir + lamivudine arm versus 85/133 in the atazanavir/ritonavir + 2NRTI arm (63.9%, 95% CI 55.7/72.1) achieved treatment success (difference between arms +13.5%, 95% CI +2.7/+24.3, P = 0.015). In the PP population, treatment success was achieved in 102/131 patients (77.9%, 95% CI 70.8/85.0) in the atazanavir/ritonavir + lamivudine arm versus 82/129 in the atazanavir/ritonavir + 2NRTI arm (63.6%, 95% CI 55.3/71.9) (difference between arms +14.3%, 95% CI +3.4/+25.2, P = 0.011) (Figure 2). Detailed causes of treatment failure are reported in Table 2. As reported, during the first 48 weeks, there were two and six virological failures in the atazanavir/ritonavir + lamivudine arm and the atazanavir/ritonavir + 2NRTI arm, respectively;8 between weeks 49 and 96, three additional virological failures were observed with atazanavir/ritonavir + 2NRTI and none with atazanavir/ritonavir + lamivudine. Therefore, at week 96 there were more virological failures in the triple therapy arm [n = 9 (6.8%)] compared with the dual therapy arm [n = 2 (1.5%), P = 0.060] (see Table S1, available as Supplementary data at JAC Online, for details). Nine of 11 (81.8%) virological failures were successfully genotyped, both failures of the atazanavir/ritonavir + lamivudine arm and 7/9 of the atazanavir/ritonavir + 2NRTI arm: no significant resistance to any of the ongoing drugs was detected. Plasma samples for measurement of atazanavir levels at failure were available in 9/11 patients (2/2 in atazanavir/ritonavir + lamivudine and 7/9 in the atazanavir/ritonavir + 2NRTI). Undetectable atazanavir levels (<0.05 mg/L) were found in 1/2 (50%) and 3/7 (42.9%) plasma samples in the dual-therapy arm and the triple-therapy arm, respectively; in the remaining patients, the atazanavir concentration was above the suggested mid-dosing interval or trough concentration efficacy cut-off.19,20 Patients showing viral blips not leading to virological failure or treatment discontinuation were less frequently found in the dual-therapy arm, but the difference with the comparator arm was not statistically significant [n = 11 (8.3%) in the atazanavir/ritonavir + lamivudine arm and n = 20 (15.0%) in the atazanavir/ritonavir + 2NRTI arm, P = 0.085]. Table 2. Causes of treatment failure after 96 weeks ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P Any cause 30 (22.6) 46 (34.6) 0.030 Virological failure 2 (1.5) 9 (6.8) 0.060 Adverse events (potentially treatment related) 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow-up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P Any cause 30 (22.6) 46 (34.6) 0.030 Virological failure 2 (1.5) 9 (6.8) 0.060 Adverse events (potentially treatment related) 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow-up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n (%). Values in bold are statistically significant. Table 2. Causes of treatment failure after 96 weeks ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P Any cause 30 (22.6) 46 (34.6) 0.030 Virological failure 2 (1.5) 9 (6.8) 0.060 Adverse events (potentially treatment related) 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow-up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P Any cause 30 (22.6) 46 (34.6) 0.030 Virological failure 2 (1.5) 9 (6.8) 0.060 Adverse events (potentially treatment related) 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow-up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n (%). Values in bold are statistically significant. The proportion of treatment failure due to potentially treatment-related or not-treatment-related adverse events was similar in both arms. HIV-DNA levels To monitor changes in the magnitude of the HIV-1 cellular reservoir, blood-associated HIV-DNA levels were quantified both at baseline and at week 96 in a subset of 140 patients. Mean baseline HIV-DNA levels (log10 copies/106 leucocytes) were comparable in the atazanavir/ritonavir + lamivudine arm (2.42, 95% CI 2.32/2.54) and the atazanavir/ritonavir + 2NRTI arm (2.37, 95% CI 2.24/2.51) (P = 0.570). Outcomes at 48 weeks have been presented elsewhere.21 At 96 weeks, a significant decrease from baseline in HIV-DNA (log10 copies/106 leucocytes) was observed in both arms: −0.15 (95% CI −0.23/−0.07, P < 0.001) in the dual-therapy arm versus −0.18 (95% CI −0.27/−0.08, P < 0.001) in the control arm, without significant differences between the two arms (P = 0.703). Clinical adverse events The proportion of patients with at least one clinical adverse event of any grade did not differ between arms and there were no significant differences regarding the types of events, although the atazanavir/ritonavir + 2NRTI arm tended to show a higher number of renal adverse events (Table 3). Most adverse events were mild to moderate. Table 3. Proportion of patients with clinical adverse events of any grade during 96 week follow-up ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P CNS 4 (3.0) 6 (4.5) 0.749 Gastrointestinal 13 (9.8) 10 (7.5) 0.513 Skin and soft tissues 7 (5.3) 1 (0.8) 0.066 Urinary tract 7 (5.3) 12 (9.0) 0.234 Respiratory tract 10 (7.5) 9 (6.8) 0.812 Infections 22 (16.5) 26 (19.5) 0.524 Neoplasm 5 (3.8) 3 (2.3) 0.722 Bone 6 (4.5) 9 (6.8) 0.425 Other 21 (15.8) 22 (16.5) 0.868 Patients with at least one adverse event 52 (39.1) 52 (39.1) 1.000 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P CNS 4 (3.0) 6 (4.5) 0.749 Gastrointestinal 13 (9.8) 10 (7.5) 0.513 Skin and soft tissues 7 (5.3) 1 (0.8) 0.066 Urinary tract 7 (5.3) 12 (9.0) 0.234 Respiratory tract 10 (7.5) 9 (6.8) 0.812 Infections 22 (16.5) 26 (19.5) 0.524 Neoplasm 5 (3.8) 3 (2.3) 0.722 Bone 6 (4.5) 9 (6.8) 0.425 Other 21 (15.8) 22 (16.5) 0.868 Patients with at least one adverse event 52 (39.1) 52 (39.1) 1.000 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n (%). Grade 3–4 clinical adverse events: nine in the dual-therapy arm [two sudden deaths (probably cardiac), thyroid carcinoma, melanoma, atrial fibrillation, bronchitis, asthma, biliary colic and pancreatitis; the last two events were considered treatment related] and nine in the triple-therapy arm (abdominal cancer, prostate adenocarcinoma, pneumonia, radiculitis, traumatic tibia fracture, finger amputation, pregnancy, cervicitis and renal colic; the last event was considered treatment related). Table 3. Proportion of patients with clinical adverse events of any grade during 96 week follow-up ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P CNS 4 (3.0) 6 (4.5) 0.749 Gastrointestinal 13 (9.8) 10 (7.5) 0.513 Skin and soft tissues 7 (5.3) 1 (0.8) 0.066 Urinary tract 7 (5.3) 12 (9.0) 0.234 Respiratory tract 10 (7.5) 9 (6.8) 0.812 Infections 22 (16.5) 26 (19.5) 0.524 Neoplasm 5 (3.8) 3 (2.3) 0.722 Bone 6 (4.5) 9 (6.8) 0.425 Other 21 (15.8) 22 (16.5) 0.868 Patients with at least one adverse event 52 (39.1) 52 (39.1) 1.000 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P CNS 4 (3.0) 6 (4.5) 0.749 Gastrointestinal 13 (9.8) 10 (7.5) 0.513 Skin and soft tissues 7 (5.3) 1 (0.8) 0.066 Urinary tract 7 (5.3) 12 (9.0) 0.234 Respiratory tract 10 (7.5) 9 (6.8) 0.812 Infections 22 (16.5) 26 (19.5) 0.524 Neoplasm 5 (3.8) 3 (2.3) 0.722 Bone 6 (4.5) 9 (6.8) 0.425 Other 21 (15.8) 22 (16.5) 0.868 Patients with at least one adverse event 52 (39.1) 52 (39.1) 1.000 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n (%). Grade 3–4 clinical adverse events: nine in the dual-therapy arm [two sudden deaths (probably cardiac), thyroid carcinoma, melanoma, atrial fibrillation, bronchitis, asthma, biliary colic and pancreatitis; the last two events were considered treatment related] and nine in the triple-therapy arm (abdominal cancer, prostate adenocarcinoma, pneumonia, radiculitis, traumatic tibia fracture, finger amputation, pregnancy, cervicitis and renal colic; the last event was considered treatment related). There were 18 grade 3 or 4 clinical adverse events: 9 per arm, but only 3 were considered treatment related (see Table 3 footnotes for details). Two sudden deaths, probably from cardiac disease, occurred in the atazanavir/ritonavir + lamivudine arm, both were not considered treatment related. Two malignant cancers were diagnosed during the study in each study arm (thyroid carcinoma and melanoma in the atazanavir/ritonavir + lamivudine arm; abdominal cancer and prostate adenocarcinoma in the atazanavir/ritonavir + 2NRTI arm). Overall, eight renal colics occurred during 96 weeks (two in the atazanavir/ritonavir + lamivudine arm and six in the atazanavir/ritonavir + 2NRTI arm); these led to treatment discontinuation in five cases (two in the atazanavir/ritonavir + lamivudine arm and three in the atazanavir/ritonavir + 2NRTI arm). Laboratory toxicity and evolution of laboratory parameters A significantly higher number of patients randomized to atazanavir/ritonavir + lamivudine showed at least one grade 3 or 4 laboratory adverse event (79.9% versus 67.7% in the triple-therapy arm, P = 0.026) (Table 4). This excess was mainly attributable to a higher frequency of hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) in the dual-therapy arm. However, no patient discontinued the regimen for grade 3 or 4 laboratory adverse events. Indeed, grade 1 or 2 laboratory adverse events led to treatment discontinuation in two (1.5%) patients in the atazanavir/ritonavir + lamivudine arm (one grade 2 hypertriglyceridaemia, one grade 1 creatinine increase) and five (3.8%) patients in the atazanavir/ritonavir + 2NRTI arm (one grade 2 hyperbilirubinemia, three grade 1 creatinine increase and one grade 1 proteinuria) (P = 0.447). Table 4. Proportion of patients with grade 3–4 laboratory toxicities Total grade 3–4 toxicities Newa grade 3–4 toxicities ATV/RTV + 3TC ATV/RTV + 2NRTI P ATV/RTV + 3TC ATV/RTV + 2NRTI P Total cholesterol 8/133 (6.0) 4/133 (3.0) 0.237 6/126 (4.8) 2/126 (1.6) 0.281 LDL cholesterol 19/133 (14.3) 11/133 (8.3) 0.121 12/111 (10.8) 7/115 (6.1) 0.201 Triglycerides 9/133 (6.8) 2/133 (1.5) 0.031 9/126 (7.1) 2/128 (1.6) 0.029 Total bilirubin 89/133 (66.9) 67/133 (50.4) 0.006 59/99 (59.6) 37/99 (37.4) 0.002 ALT 0/133 (0) 2/133 (1.5) 0.156 0/129 (0) 1/128 (0.8) 0.314 At least one laboratory toxicity 106/133 (79.7) 90/133 (67.7) 0.026 76/133 (57.1) 57/133 (42.9) 0.027 Total grade 3–4 toxicities Newa grade 3–4 toxicities ATV/RTV + 3TC ATV/RTV + 2NRTI P ATV/RTV + 3TC ATV/RTV + 2NRTI P Total cholesterol 8/133 (6.0) 4/133 (3.0) 0.237 6/126 (4.8) 2/126 (1.6) 0.281 LDL cholesterol 19/133 (14.3) 11/133 (8.3) 0.121 12/111 (10.8) 7/115 (6.1) 0.201 Triglycerides 9/133 (6.8) 2/133 (1.5) 0.031 9/126 (7.1) 2/128 (1.6) 0.029 Total bilirubin 89/133 (66.9) 67/133 (50.4) 0.006 59/99 (59.6) 37/99 (37.4) 0.002 ALT 0/133 (0) 2/133 (1.5) 0.156 0/129 (0) 1/128 (0.8) 0.314 At least one laboratory toxicity 106/133 (79.7) 90/133 (67.7) 0.026 76/133 (57.1) 57/133 (42.9) 0.027 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n/N (%). Values in bold are statistically significant. a Incident toxicity, not present at baseline. Table 4. Proportion of patients with grade 3–4 laboratory toxicities Total grade 3–4 toxicities Newa grade 3–4 toxicities ATV/RTV + 3TC ATV/RTV + 2NRTI P ATV/RTV + 3TC ATV/RTV + 2NRTI P Total cholesterol 8/133 (6.0) 4/133 (3.0) 0.237 6/126 (4.8) 2/126 (1.6) 0.281 LDL cholesterol 19/133 (14.3) 11/133 (8.3) 0.121 12/111 (10.8) 7/115 (6.1) 0.201 Triglycerides 9/133 (6.8) 2/133 (1.5) 0.031 9/126 (7.1) 2/128 (1.6) 0.029 Total bilirubin 89/133 (66.9) 67/133 (50.4) 0.006 59/99 (59.6) 37/99 (37.4) 0.002 ALT 0/133 (0) 2/133 (1.5) 0.156 0/129 (0) 1/128 (0.8) 0.314 At least one laboratory toxicity 106/133 (79.7) 90/133 (67.7) 0.026 76/133 (57.1) 57/133 (42.9) 0.027 Total grade 3–4 toxicities Newa grade 3–4 toxicities ATV/RTV + 3TC ATV/RTV + 2NRTI P ATV/RTV + 3TC ATV/RTV + 2NRTI P Total cholesterol 8/133 (6.0) 4/133 (3.0) 0.237 6/126 (4.8) 2/126 (1.6) 0.281 LDL cholesterol 19/133 (14.3) 11/133 (8.3) 0.121 12/111 (10.8) 7/115 (6.1) 0.201 Triglycerides 9/133 (6.8) 2/133 (1.5) 0.031 9/126 (7.1) 2/128 (1.6) 0.029 Total bilirubin 89/133 (66.9) 67/133 (50.4) 0.006 59/99 (59.6) 37/99 (37.4) 0.002 ALT 0/133 (0) 2/133 (1.5) 0.156 0/129 (0) 1/128 (0.8) 0.314 At least one laboratory toxicity 106/133 (79.7) 90/133 (67.7) 0.026 76/133 (57.1) 57/133 (42.9) 0.027 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n/N (%). Values in bold are statistically significant. a Incident toxicity, not present at baseline. The evolution of CD4 and serum biochemical parameters from baseline to 96 weeks is illustrated in Figure 3. Mean changes in CD4 count did not differ between arms (+77 cells/mm3 with atazanavir/ritonavir + lamivudine versus +49 cells/mm3 with atazanavir/ritonavir + 2NRTI, P = 0.306). Mean changes in total cholesterol levels were +16 mg/dL in the atazanavir/ritonavir + lamivudine arm and +0 mg/dL in the atazanavir/ritonavir + 2NRTI arm (P = 0.002), with a concomitant increase in LDL cholesterol (+13 mg/dL with atazanavir/ritonavir + lamivudine versus +4 mg/dL with atazanavir/ritonavir + 2NRTI, P = 0.092) and HDL cholesterol (+5 mg/dL with atazanavir/ritonavir + lamivudine versus +0 mg/dL with atazanavir/ritonavir + 2NRTI, P = 0.002); as a result, modifications of total/HDL cholesterol (+3.1 versus +0.7, P = 0.361) and HDL/LDL cholesterol (0 versus −0.1, P = 0.730) ratios from baseline to 96 weeks did not differ between arms. At 96 weeks, renal function showed a significant improvement in the atazanavir/ritonavir + lamivudine versus the atazanavir/ritonavir + 2NRTI arm with a mean change from baseline eGFRMDRD of +5 mL/min/1.73 m2 versus −2 mL/min/1.73 m2, respectively (P < 0.001) (where eGFR stands for estimated glomerular filtration rate and MDRD stands for Modification of Diet in Renal Disease Study Equation). Conversely, a slight increase in total bilirubin levels was observed in the dual-therapy arm (+0.2 versus −0.1 mg/dL, P = 0.039). Figure 3. View largeDownload slide Mean change from baseline values at week 96 in (a) peripheral blood CD4 T cell counts, (b) blood lipids, (c) eGFR and (d) bilirubin values in the two treatment arms. ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TC, total cholesterol; LDL, LDL cholesterol; HDL, HDL cholesterol; TG, triglyceride; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration formula; MDRD, Modification of Diet in Renal Disease Study Equation. Figure 3. View largeDownload slide Mean change from baseline values at week 96 in (a) peripheral blood CD4 T cell counts, (b) blood lipids, (c) eGFR and (d) bilirubin values in the two treatment arms. ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TC, total cholesterol; LDL, LDL cholesterol; HDL, HDL cholesterol; TG, triglyceride; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration formula; MDRD, Modification of Diet in Renal Disease Study Equation. Neurocognitive performance Neurocognitive data at 96 weeks were available for 107 patients (40.2% on the total), 56 in the study arm and 51 in the control arm. At baseline, patients in the two arms did not differ in terms of their main characteristics (data not shown) and showed a comparable proportion of cognitive impairment (10.7% in the atazanavir/ritonavir + lamivudine arm versus 21.7% in the atazanavir/ritonavir + 2NRTI arm, all with a profile of asymptomatic cognitive impairment,16P = 0.185). At 96 weeks, the two groups confirmed no difference in the prevalence of cognitive impairment (14.3% versus 13.7%, respectively, P = 1.000). Analysing each arm separately, both groups confirmed no change in the prevalence of cognitive impairment at 96 weeks in comparison with baseline (atazanavir/ritonavir + lamivudine arm: 14.3% versus 10.7%, P = 0.625; atazanavir/ritonavir + 2NRTI arm: 13.7% versus 21.7%, P = 0.219). Bone health and body fat distribution Bone mineral density, body fat distribution (as measured by DEXA scan) and biomarkers of bone metabolism were available at baseline and 96 weeks for 91 (34.2%) patients (52 in the atazanavir/ritonavir + lamivudine arm and 39 in the atazanavir/ritonavir + 2NRTI arm). At baseline, bone loss at any site (in terms of osteopenia or osteoporosis) was diagnosed in 61.5% (n = 56) of patients, of which 34/52 (65.4%) were in the atazanavir/ritonavir + lamivudine arm and 22/39 (56.4%) were in the atazanavir/ritonavir + 2NRTI arm (P = 0.384). At 96 weeks, we observed a significantly higher increase in lumbar spine bone mineral density in dual therapy (mean change versus baseline +4.2% versus −2.5% in the triple-therapy arm, P = 0.021), with no differences in total hip and femoral neck bone mineral density between arms (Table S2). Evaluating bone biomarkers, a significant reduction in parathyroid hormone levels was observed in the atazanavir/ritonavir + lamivudine arm (−9.4 versus +0.9 pg/mL in the atazanavir/ritonavir + 2NRTI arm, P = 0.008); no significant between-arm differences were observed for the other bone biomarkers. Exploring body fat distribution, at 96 weeks no significant differences between the two arms were observed in terms of change in limb or trunk fat and lean mass (Table S2). Adherence During the study, adherence data were provided by 254 (95.5%) patients [130 (97.7%) in the atazanavir/ritonavir + lamivudine arm and 124 (93.2%) in the atazanavir/ritonavir + 2NRTI arm, P = 0.137]. At baseline, adherence was similar in the two arms [mean: 86% (SD 18) in the atazanavir/ritonavir + lamivudine arm and 88% (SD 14) in the atazanavir/ritonavir + 2NRTI arm, P = 0.306]. During the entire follow-up, no significant differences were observed in terms of adherence levels at any study visit [mean change versus baseline at 96 weeks: +2% (SD 18) in the atazanavir/ritonavir + lamivudine arm and −1% (SD 15) in the atazanavir/ritonavir + 2NRTI arm, P = 0.312]. Discussion Studies investigating a treatment switch to dual therapy with a boosted PI plus lamivudine in virologically suppressed HIV-infected patients have shown promising results,5,8,9 but few data are available about the efficacy of this strategy over the long term.7,10 Moreover, real benefits in terms of reduced toxicity have not been completely demonstrated and concerns remain about reduced activity in sanctuary sites (e.g. the CNS). At 96 weeks, the results of the ATLAS-M trial confirm the non-inferiority of treatment simplification to atazanavir/ritonavir + lamivudine versus continuing an atazanavir/ritonavir-based triple therapy in virologically suppressed patients. Moreover, a post hoc superiority of this dual therapy was demonstrated by all types of analyses performed. This result was driven by several factors, including lower discontinuation rates for adverse events (both treatment and not treatment related), less frequent withdrawal of consent but also, most importantly, by lower rates of virological failure in the atazanavir/ritonavir + lamivudine arm. Only two virological failures (one of which occurred at baseline before the treatment switch) were observed with the dual therapy during the first 48 weeks and no further virological failure occurred thereafter. Moreover, no emerging HIV-1 drug resistance was observed at failure in both arms. These results confirm the efficacy over the long term of treatment simplification to atazanavir/ritonavir + lamivudine in virologically suppressed patients with very low risk of virological failure and absence of resistance in the case of failure. Regarding tolerability, patients switched to atazanavir/ritonavir + lamivudine showed a significant recovery of eGFR when compared with those continuing triple therapy, suggesting that this regimen could halt the deterioration of renal function. This observation can be ascribed to the discontinuation of tenofovir disoproxil fumarate in the majority of patients randomized to the dual-therapy arm. Whether a similar result could be obtained with a switch to a tenofovir alafenamide-containing backbone remains to be determined as no studies have yet directly compared tenofovir alafenamide with dual therapies.22 The discontinuation of tenofovir disoproxil fumarate could also explain the improvements in lumbar spine bone mineral density23 observed in the atazanavir/ritonavir + lamivudine arm, while patients treated with atazanavir/ritonavir + 2NRTI worsened; as expected after tenofovir disoproxil fumarate discontinuation,24 we also observed a reduction in parathyroid hormone levels in the dual-therapy arm, which might have been translated into a lower bone resorption. Patients switched to dual therapy showed a slight increase in total cholesterol but also HDL cholesterol; this can be ascribed to the discontinuation of tenofovir disoproxil fumarate, which has a known lipid-lowering effect.25,26 However, total/HDL cholesterol and HDL/LDL cholesterol ratios remained unchanged and, as a consequence, the impact on the cardiovascular risk is expected to be negligible. In the dual-therapy arm, we observed a higher proportion of patients developing grade 3 or 4 increases in bilirubin and triglyceride levels, but this did not impact the tolerability of the regimens since treatment discontinuations for laboratory adverse events were similar between arms. A potential explanation for higher bilirubin levels in the dual-therapy arm could be an increase in atazanavir plasma concentration due to tenofovir disoproxil fumarate discontinuation, which occurred in the majority of patients, as suggested by drug–drug interaction studies.27 A supposed drawback of dual therapy is potential concern about reduced efficacy in controlling viral replication in sanctuary sites. To assess this issue in ATLAS-M, total HIV-DNA level, a surrogate marker of viral replication in reservoirs,28 was measured during the study. At 96 weeks, we observed a significant decrease in total HIV-DNA levels in both arms, without any significant between-arm differences. This observation confirms results obtained at 48 weeks21 and offers a degree of reassurance about the ability of this dual regimen in controlling viral replication in reservoirs over the long term. Another concern about simplification to dual therapies is the potential for inadequate drug activity in the CNS. Importantly, in our study no significant difference in the prevalence of neurocognitive impairment was observed between the two study arms at 96 weeks, suggesting a CNS-safe profile of simplification to atazanavir/ritonavir + lamivudine, at least in the medium term, in subjects with stable plasma viral load control and without symptomatic neurocognitive impairment. Treatment simplification to atazanavir/ritonavir + lamivudine in virologically suppressed patients has also been investigated by the SALT trial, which demonstrated non-inferior efficacy (although not superiority) at 96 weeks of the dual therapy over an atazanavir/ritonavir-based triple therapy, without any benefit in terms of tolerability.10 The SALT and ATLAS-M trials were slightly different regarding study design and this could explain why superior efficacy and better renal tolerability of atazanavir/ritonavir + lamivudine were not shown in the SALT trial. The SALT trial enrolled patients on any ART regimen and allowed switching of the NRTI backbone at baseline in those with tolerability issues, thus efficacy results relied also on tolerability of drugs not previously taken by patients. In the ATLAS-M trial, all patients were treated with atazanavir/ritonavir + 2NRTI before baseline, and therefore those randomized to dual therapy simply removed an NRTI from their standard triple-therapy regimen. In this way, the study design of the ATLAS-M trial more accurately reflects what happens when an NRTI drug is removed from a standard triple-therapy regimen, both in terms of efficacy and tolerability. Some limitations should be acknowledged when interpreting the results of our study. Since this is an open-label study, physicians could have been more prone to discontinue treatment if toxicity occurred and this could have partly influenced the main outcome. However, this potential bias does not influence virological outcome, which was favourable with dual therapy. It should also be emphasized that patients included in the ATLAS-M study were accurately selected according to strict inclusion and exclusion criteria, meaning that results cannot be generalized to all HIV-infected patients. In particular, this dual regimen should not be prescribed to patients without stable virological suppression, with a low CD4 count, with previous episodes of virological failure or with coinfection with HBV, as for all other tenofovir-sparing regimens. In conclusion, in the ATLAS-M trial, the safety and efficacy of treatment simplification to atazanavir/ritonavir + lamivudine in virologically suppressed patients were confirmed over 96 weeks, with a post hoc superiority of dual therapy over a standard triple-therapy regimen. A sustained benefit in terms of preserved renal function and improvement in lumbar spine bone mineral density was observed, without other significant laboratory concerns. Of note, no concerns about the efficacy of dual therapy in sanctuary sites emerged during the 96 weeks of the trial, as demonstrated by the constant decrease in total blood HIV-DNA levels and by the evolution of cognitive performance. These promising efficacy and safety data of atazanavir/ritonavir + lamivudine, together with a potential for substantial cost reduction of ART,29,30 especially if generic drugs are used, make this regimen a suitable option for treatment simplification. Acknowledgements Preliminary data were presented at the HIV Drug Therapy Glasgow Congress 2016 (Abstract P086).  We would like to thank the ATLAS-M study participants for taking part in this trial, the ATLAS-M investigators and their staff for contributing to the realization of this study and the external contract research organization for its assistance during the study. Members of the ATLAS-M Study Group R. Cauda, S. Di Giambenedetto, M. Fabbiani, A. Mondi, N. Ciccarelli, A. Borghetti, E. Baldonero, S. Belmonti, A. D’Avino, R. Gagliardini, S. Lamonica, F. Lombardi, L. Sidella, E. Tamburrini, E. Visconti (Istituto di Clinica delle Malattie Infettive, Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli); A. De Luca (Clinica di Malattie Infettive, Università degli Studi di Siena); A. Giacometti, F. Barchiesi, P. Castelli, O. Cirioni, S. Mazzocato (Struttura Organizzativa Dipartimentale Clinica di Malattie infettive, Azienda Ospedaliero Universitaria—Ospedali Riuniti di Ancona); M. Di Pietro, P. Blanc, A. Degli Esposti, B. Del Pin, E. Mariabelli, S. Marini, A. Poggi (UO Malattie Infettive, Ospedale S. M. Annunziata Firenze); E. Quiros Roldan, E. Focà, S. Amadasi, A. Apostoli, L. Biasi, A. Bonito, N. Brianese, S. Compostella, A. Ferraresi, D. Motta (Istituto di Malattie Infettive e Tropicali, Università di Brescia—Azienda Ospedaliera Spedali Civili, Brescia); M.T. Mughini, B.M. Celesia, M. Gussio, S. Sofia (Istituto Malattie Infettive, ARNAS Garibaldi PO Nesima); P. Grima, M. Tana, P. Tundo (UOC di Malattie Infettive, PO ‘S. Caterina Novella’); C. Viscoli, L. De Hoffer, A. Di Biagio, S. Grignolo, A. Parisini, E. Schenone, L. Taramasso (Clinica Malattie Infettive, Azienda Ospedaliera Universitaria San Martino Genova); P.E. Manconi, A. Boccone, F. Ortu, P. Piano, L. Serusi (Centro di Immunologia, AO Universitaria—Cagliari); M. Puoti, M. C. Moioli, R. Rossotti, G. Travi, F. Ventura (Istituto di Malattie Infettive, AO Ospedale Niguarda Cà Granda Milano); M. Galli, S. Rusconi, S. Di Nardo Stuppino, V. Di Cristo, A. Giacomelli, V. Vimercati (Dip. di Scienze Cliniche L. Sacco/Sez. Malattie Infettive, Ospedale Luigi Sacco di Milano Azienda ospedaliera e Polo Universitario); P. Viale (UO Malattie infettive, Policlinico S. Orsola Malpighi Bologna); A. Gori (UO Malattie infettive, Azienda Ospedaliera San Gerardo Monza); G. Rizzardini, A. Capetti, L. Carenzi, F. Mazza, P. Meraviglia, S. Rosa, P. Zucchi (Malattie infettive I Divisione, Ospedale Luigi Sacco di Milano); M. Mineo (Istituto di Malattie Infettive, AO Universitaria Policlinico Paolo Giaccone di Palermo); A. Latini, M. Colafigli, M. Giuliani, A. Pacifici, F. Pimpinelli, F. Solivetti, F. Stivali (UOC Dermatologia Infettiva, IRCCS Istituto Dermatologico S. Gallicano IFO); A. Antinori, F. Angelici, R. Bellagamba, D. Delle Rose, R. Fezza, R. Libertone, S. Mosti, P. Narciso, E. Nicastri, S. Ottou, C. Tomassi, C. Vlassi, M. Zaccarelli, F. Zoppè (UOC Malattie Infettive e Tropicali IV Divisione, INMIL Spallanzani IRCCS); V. Vullo, G. D’Ettorre, F. Altavilla, G. Ceccarelli, A. Fantauzzi, S. Gebremeskel, S. Lo Menzo, I. Mezzaroma, F. Tierno (Dipartimento di Malattie Infettive e Tropicali, Università degli studi di Roma La Sapienza); N. Petrosillo, P. Chinello, E. Boumis, S. Cicalini, E. Grilli, M. Musso, C. Stella (UOC Infezioni Sistemiche e dell'Immunodepresso II Divisione, INMIL Spallanzani IRCCS); M. S. Mura, G. Madeddu, P. Bagella, M. Mannazzu, V. Soddu (Reparto Malattie Infettive, Università degli studi di Sassari); P. Caramello, G. Orofino, C. Carcieri, S. Carosella, M. Farenga (Divisione A Malattie Infettive, Ospedale Amedeo di Savoia); P. G. Scotton, M. C. Rossi (UO Malattie infettive, Azienda ULSS 9 Treviso Ospedale S. Maria di Ca'Foncello); E. Concia, F. Corsini, C. Gricolo, M. Lanzafame, E. Lattuada, S. Leonardi, F. Rigo (UOC Malattie infettive, Azienda Ospedaliera Universitaria Integrata di Verona); A. Lazzarin, A. Castagna, A. Bigoloni, E. Carini, S. Nozza, V. Spagnuolo (Malattie infettive, Ospedale San Raffaele Milano); D. Francisci, B. Belfiori, L. Malincarne, E. Schiaroli, C. Sfara, A. Tosti (Clinica di Malattie Infettive, Ospedale S. Maria della Misericordia Perugia); D. Sacchini, A. Ruggieri, C. Valdatta (UO Malattie infettive—Dipartimento Medicina Specialistica, Ospedale Guglielmo Da Saliceto Ausl Di Piacenza). Funding This work was supported by Bristol-Myers Squibb, which provided an unrestricted grant to the Catholic University of Sacred Heart (the sponsor) and one of the study drugs (atazanavir) for the experimental arm. Transparency declarations M. F. has received speakers’ honoraria and support for travel to meetings from Bristol-Myers Squibb (BMS), Gilead, Merck Sharp & Dohme (MSD), ViiV Healthcare and Janssen-Cilag, and has received fees for attending advisory boards from BMS and Gilead. R. G. has received support for travel from Gilead and Janssen-Cilag. E. Q. R. has received grants from Gilead and ViiV, and has received personal fees from Gilead, BMS, MSD, Janssen-Cilag and ViiV. A. L. has received support for travel from Gilead, BMS and Janssen-Cilag. A. A. has received personal fees from BMS, Gilead, Merck, ViiV, AbbVie and Janssen-Cilag, and has received grants from BMS, Gilead, ViiV and Janssen-Cilag. G. O. has received personal fees from Gilead and ViiV. P. C. has received grants from Pfizer. S. R. has received personal fees from AbbVie, Gilead, ViiV, Janssen, BMS and MSD, and has received grants from Gilead, ViiV and Janssen-Cilag. A. D. has received travel grants from MSD, Gilead, BMS and ViiV Healthcare. E. F. has received personal fees from Gilead, BMS, MSD, Janssen-Cilag and ViiV, and has received grants from Gilead and ViiV. M. C. has received support for travel from Gilead, BMS and Janssen-Cilag. R. C. has been an advisor for Gilead, Janssen-Cilag and Basel Pharmaceutical, and has received speakers’ honoraria from ViiV, BMS, MSD, Abbott, Gilead and Janssen-Cilag. S. D. G. has received speakers’ honoraria and support for travel to meetings from Gilead, BMS, Abbott, Boehringer Ingelheim, Janssen-Cilag and GlaxoSmithKline. A. D. L. has received speaker’s honoraria and fees for attending advisory boards from ViiV, Gilead, AbbVie, Janssen-Cilag, MSD and BMS, and has received unrestricted research grants (to his institution) from ViiV Italy, Gilead Sciences (Fellowship Programme) and MSD Italy. All other authors: none to declare. Author contributions S. D. G., R. C. and A. D. L. designed the study, analysed the data and finalized the drafting of the paper. M. F. analysed the data and contributed to the literature search and article drafting. All other authors were responsible for data collection and adverse event reports for the respective enrolling centres. Supplementary data Tables S1 and S2 are available as Supplementary data at JAC Online. References 1 Arribas JR , Girard P-M , Paton N et al. Efficacy of protease inhibitor monotherapy vs. triple therapy: meta-analysis of data from 2303 patients in 13 randomized trials . HIV Med 2016 ; 17 : 358 – 67 . Google Scholar CrossRef Search ADS PubMed 2 Nozza S , Svicher V , Saracino A et al. State of the art of dual therapy in 2015 . AIDS Rev 2015 ; 17 : 127 – 34 . Google Scholar PubMed 3 Latini A , Fabbiani M , Borghi V et al. Switching to boosted protease inhibitor plus a second antiretroviral drug (dual therapy) for treatment simplification: a multicenter observational study . BMC Infect Dis 2016 ; 16 : 401. Google Scholar CrossRef Search ADS PubMed 4 Cahn P , Andrade-Villanueva J , Arribas JR et al. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomise . Lancet Infect Dis 2014 ; 14 : 572 – 80 . Google Scholar CrossRef Search ADS PubMed 5 Arribas JR , Girard P-M , Landman R et al. Dual treatment with lopinavir–ritonavir plus lamivudine versus triple treatment with lopinavir–ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial . Lancet Infect Dis 2015 ; 15 : 785 – 92 . Google Scholar CrossRef Search ADS PubMed 6 Di Giambenedetto S , Fabbiani M , Colafigli M et al. Safety and feasibility of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitors + atazanavir/ritonavir with virological suppression (Atazanavir and Lamivudine for treatment Simplification, AtLaS pilot study) . J Antimicrob Chemother 2013 ; 68 : 1364 – 72 . Google Scholar CrossRef Search ADS PubMed 7 Mondi A , Fabbiani M , Ciccarelli N et al. Efficacy and safety of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression: 144 week follow-up of the AtLaS pilot study . J Antimicrob Chemother 2015 ; 70 : 1843 – 9 . Google Scholar CrossRef Search ADS PubMed 8 Di Giambenedetto S , Fabbiani M , Quiros Roldan E et al. Treatment simplification to atazanavir/ritonavir + lamivudine versus maintenance of atazanavir/ritonavir + two NRTIs in virologically suppressed HIV-1-infected patients: 48 week results from a randomized trial (ATLAS-M) . J Antimicrob Chemother 2017 ; 72 : 1163 – 71 . Google Scholar PubMed 9 Perez-Molina JA , Rubio R , Rivero A et al. Dual treatment with atazanavir–ritonavir plus lamivudine versus triple treatment with atazanavir–ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week results from a randomised, open-label, non-inferiority trial . Lancet Infect Dis 2015 ; 15 : 775 – 84 . Google Scholar CrossRef Search ADS PubMed 10 Perez-Molina JA , Rubio R , Rivero A et al. Simplification to dual therapy (atazanavir/ritonavir + lamivudine) versus standard triple therapy [atazanavir/ritonavir + two nucleos(t)ides] in virologically stable patients on antiretroviral therapy: 96 week results from an open-label, non-inferiority, randomized clinical trial (SALT study) . J Antimicrob Chemother 2017 ; 72 : 246 – 53 . Google Scholar CrossRef Search ADS PubMed 11 Casado JL , Banon S , Rodriguez MA et al. Efficacy of dual therapy with lamivudine plus darunavir boosted with ritonavir once daily in HIV-infected patients with nucleoside analogue toxicity . J Antimicrob Chemother 2015 ; 70 : 630. Google Scholar CrossRef Search ADS PubMed 12 Fabbiani M , Di Giambenedetto S , Poli A et al. Simplification to a dual regimen with darunavir/ritonavir plus lamivudine or emtricitabine in virologically-suppressed HIV-infected patients . J Infect 2016 ; 73 : 619 – 23 . Google Scholar CrossRef Search ADS PubMed 13 Pulido F , Ribera E , Lagarde M et al. Dual therapy with darunavir and ritonavir plus lamivudine versus triple therapy with darunavir and ritonavir plus tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine for maintenance of HIV-1 viral suppression: randomised, open label, noninferiority DUAL-GESIDA 8014-RIS-EST45 Trial . Clin Infect Dis 2017 ; 65 : 2112 – 8 . Google Scholar CrossRef Search ADS PubMed 14 Murri R , Cingolani A , De Luca A et al. Asymmetry of the regimen is correlated to self-reported suboptimal adherence: results from AdUCSC, a cohort study on adherence in Italy . J Acquir Immune Defic Syndr 2010 ; 55 : 411 – 2 . Google Scholar CrossRef Search ADS PubMed 15 Brown TT , Hoy J , Borderi M et al. Recommendations for evaluation and management of bone disease in HIV . Clin Infect Dis 2015 ; 60 : 1242 – 51 . Google Scholar CrossRef Search ADS PubMed 16 Antinori A , Arendt G , Becker JT et al. Updated research nosology for HIV-associated neurocognitive disorders . Neurology 2007 ; 69 : 1789 – 99 . Google Scholar CrossRef Search ADS PubMed 17 Viard J-P , Burgard M , Hubert J-B et al. Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level . AIDS 2004 ; 18 : 45 – 9 . Google Scholar CrossRef Search ADS PubMed 18 Fabbiani M , Di Giambenedetto S , Bracciale L et al. Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice . J Antimicrob Chemother 2009 ; 64 : 109 – 17 . Google Scholar CrossRef Search ADS PubMed 19 Fabbiani M , Di Giambenedetto S , Ragazzoni E et al. Mid-dosing interval concentration of atazanavir and virological outcome in patients treated for HIV-1 infection . HIV Med 2010 ; 11 : 326 – 33 . Google Scholar CrossRef Search ADS PubMed 20 Gonzalez De Requena D , Bonora S , Canta F et al. Atazanavir Ctrough is associated with efficacy and safety: definition of therapeutic range. In: Abstracts of the Twelth Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, 2005. Abstract 645. Foundation for Retrovirology and Human Health, Alexandria, VA, USA. 21 Lombardi F , Belmonti S , Quiros-Roldan E et al. Evolution of blood-associated HIV-1 DNA levels after 48 weeks of switching to atazanavir/ritonavir+lamivudine dual therapy versus continuing triple therapy in the randomized AtLaS-M trial . J Antimicrob Chemother 2017 ; 72 : 2055 – 9 . Google Scholar CrossRef Search ADS PubMed 22 Arribas JR , Thompson M , Sax PE et al. Randomized, double-blind comparison of tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir, cobicistat, and emtricitabine (E/C/F) for initial HIV-1 treatment: week 144 results . J Acquir Immune Defic Syndr 2017 ; 75 : 211 – 8 . Google Scholar CrossRef Search ADS PubMed 23 Grant PM , Cotter AG. Tenofovir and bone health . Curr Opin HIV AIDS 2016 ; 11 : 326 – 32 . Google Scholar CrossRef Search ADS PubMed 24 Havens PL , Stephensen CB , Van Loan MD et al. Decline in bone mass with tenofovir disoproxil fumarate/emtricitabine is associated with hormonal changes in the absence of renal impairment when used by HIV-uninfected adolescent boys and young men for HIV preexposure prophylaxis . Clin Infect Dis 2017 ; 64 : 317 – 25 . Google Scholar CrossRef Search ADS PubMed 25 Fabbiani M , Bracciale L , Doino M et al. Lipid-lowering effect of tenofovir in HIV-infected patients . J Antimicrob Chemother 2011 ; 66 : 682. Google Scholar CrossRef Search ADS PubMed 26 Gagliardini R , Fabbiani M , Colafigli M et al. Lipid-lowering effect and changes in estimated cardiovascular risk after switching to a tenofovir-containing regimen for the treatment of HIV-infected patients . J Chemother 2017 ; 29 : 299 – 307 . Google Scholar CrossRef Search ADS PubMed 27 Taburet A-M , Piketty C , Chazallon C et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients . Antimicrob Agents Chemother 2004 ; 48 : 2091. Google Scholar CrossRef Search ADS PubMed 28 Avettand-Fènoël V , Hocqueloux L , Ghosn J et al. Total HIV-1 DNA, a marker of viral reservoir dynamics with clinical implications . Clin Microbiol Rev 2016 ; 29 : 859 – 80 . Google Scholar CrossRef Search ADS PubMed 29 Restelli U , Fabbiani M , Di Giambenedetto S et al. Budget impact analysis of the simplification to atazanavir + ritonavir + lamivudine dual therapy of HIV-positive patients receiving atazanavir-based triple therapies in Italy starting from data of the Atlas-M trial . Clinicoecon Outcomes Res 2017 ; 9 : 173 – 9 . Google Scholar CrossRef Search ADS PubMed 30 Restelli U , Fabbiani M , Di Giambenedetto S et al. Update of the budget impact analysis of the simplification to atazanavir + ritonavir + lamivudine dual therapy of HIV-positive patients receiving atazanavir-based triple therapies in Italy starting from data of the Atlas-M trial . Clinicoecon Outcomes Res 2017 ; 9 : 569 – 71 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Objectives To investigate the long-term safety and efficacy of a treatment switch to dual ART with atazanavir/ritonavir + lamivudine versus continuing a standard regimen with atazanavir/ritonavir + 2NRTI in virologically suppressed patients. Methods ATLAS-M is a 96 week open-label, randomized, non-inferiority (margin −12%) trial enrolling HIV-infected adults on atazanavir/ritonavir + 2NRTI, with stable HIV-RNA <50 copies/mL and CD4 counts >200 cells/mm3. At baseline, patients were randomized 1:1 to switch to atazanavir/ritonavir + lamivudine or to continue the previous regimen. Here, we report the 96 week efficacy and safety data. The study was registered with ClinicalTrials.gov, number NCT01599364. Results Overall, 266 subjects were enrolled (133 in each arm). At 96 weeks, in the ITT population, patients free of treatment failure totalled 103 (77.4%) with atazanavir/ritonavir + lamivudine and 87 (65.4%) with triple therapy (difference +12.0%, 95% CI +1.2/+22.8, P = 0.030), demonstrating the superiority of dual therapy. Two (1.5%) and 9 (6.8%) virological failures occurred in the dual-therapy arm and the triple-therapy arm, respectively, without development of resistance to any study drug. Clinical adverse events occurred at similar rates in both arms. A higher frequency of grade 3–4 hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) occurred with dual therapy, although this never led to treatment discontinuation. A significant improvement in renal function and lumbar spine bone mineral density occurred in the dual-therapy arm. The evolution of CD4, HIV-DNA levels and neurocognitive performance was similar in both arms. Conclusions In this randomized study, a treatment switch to atazanavir/ritonavir + lamivudine was superior over the continuation of atazanavir/ritonavir + 2NRTI in virologically suppressed patients, with a sustained benefit in terms of improved renal function and bone mineral density. Introduction In recent years, drug reduction strategies to mono/dual therapies in HIV-infected patients have been investigated in order to improve long-term ART tolerability and to reduce costs while maintaining virological efficacy.1–3 Dual therapies combining a boosted PI with lamivudine have been the most intensively investigated treatments, both in naive and in virologically suppressed patients.4–13 The combination of atazanavir/ritonavir + lamivudine has shown promising results in virologically suppressed patients: two randomized studies, SALT and ATLAS-M, demonstrated non-inferior efficacy of a treatment switch to atazanavir/ritonavir + lamivudine when compared with a standard atazanavir/ritonavir-based triple therapy after a 48 week follow-up.8,9 In ATLAS-M, atazanavir/ritonavir + lamivudine even showed superior efficacy over the comparator arm at the primary study endpoint and a benefit in terms of evolution of renal function.8 It is important to investigate whether these favourable results obtained at 48 weeks persist at longer durations. The 96 week data of SALT trial have confirmed the long-term non-inferior efficacy of treatment simplification to atazanavir/ritonavir + lamivudine with no significant benefit in terms of tolerability over triple therapy.10 Here, we report the final 96 week efficacy and safety data of the ATLAS-M trial, investigating treatment simplification to atazanavir/ritonavir + lamivudine versus continuing the baseline regimen in patients who are virologically suppressed under an atazanavir/ritonavir-based triple therapy. We also report results of patients’ neurocognitive performance, bone mineral density and body fat distribution changes as well as the evolution of peripheral blood HIV-1-DNA levels at 96 weeks in the two study arms. Methods Study design, patients and procedures The design of the ATLAS-M trial has been reported elsewhere.8 Briefly, ATLAS-M is a 96 week open-label, randomized, non-inferiority trial comparing a treatment switch to 300 mg of atazanavir boosted with 100 mg of ritonavir once daily plus 300 mg of lamivudine once daily (atazanavir/ritonavir + lamivudine arm) with continuation of a standard triple-therapy regimen with 300 mg of atazanavir boosted with 100 mg of ritonavir once daily plus two NRTIs (atazanavir/ritonavir + 2NRTI arm) in virologically suppressed patients. Adult (>18 years old), HIV-1-infected patients on an antiretroviral regimen including atazanavir/ritonavir + 2NRTI from at least 3 months, with HIV-RNA <50 copies/mL and CD4 >200 cells/mm3 from at least 6 months, no previous virological failure on or resistance to atazanavir and/or lamivudine, no previous exposure to mono/dual therapies and no HBV coinfection were randomized 1:1 at baseline to atazanavir/ritonavir + lamivudine (study arm) or to continue the standard triple therapy (atazanavir/ritonavir + 2NRTI arm). The study was powered to demonstrate non-inferior efficacy with a lower margin of 12% of the study regimen versus the control arm at the primary study outcome: absence of treatment failure at 48 weeks in the ITT exposed population.8 Follow-up study visits were planned at weeks 4 and 12 and then every 12 weeks until week 96, monitoring physical examination, routine laboratory tests (HIV-RNA, CD4 count, blood chemistry, urinalysis) and treatment adherence (on a 0–100 visual analogue scale).14 At baseline, week 48 and week 96, whole body, lumbar and hip dual-energy X-ray absorptiometry (DEXA) scans was performed in a subgroup of patients. Bone metabolism biomarkers (25-OH vitamin D, parathyroid hormone, osteocalcin, calcitonin, bone alkaline phosphatase) were also assessed at the same timepoints. Osteopenia and osteoporosis were defined according to standard criteria.15 Body fat distribution was assessed by measuring total, limb and trunk fat/lean mass. Moreover, a comprehensive neuropsychological examination was also performed at baseline, week 48 and week 96. Exclusion criteria for this substudy were: active psychiatric disorders/alcoholism or drug abuse, and linguistic difficulties for non-native patients. The following cognitive domains were investigated: Verbal Learning (Immediate and Delayed Recall of Rey’s words), Attention and Working Memory (WAIS digit span and WAIS digit symbol), Language (Fluency test), and Fine Motor Skills (Grooved Pegboard Test). Individual scores on each cognitive test were transformed into Z scores and averaged to calculate a composite domain-specific Z score; cognitive impairment was defined according to Frascati criteria.16 Total HIV-DNA was quantified in whole blood at baseline, and after 48 and 96 weeks, using a TaqMan real-time PCR technique, as previously described.17 This assay takes both integrated and non-integrated HIV-DNA forms into account. Results were expressed as the log10-transformed HIV-DNA copies/106 leucocytes to normalize the distribution. Treatment failure was defined by any of the following: virological failure, any treatment modification or discontinuation, loss to follow-up, consent withdrawal, progression to AIDS, or death from any cause. Virological failure was defined as the first of two consecutive HIV-RNA levels >50 copies/mL or a single level >1000 copies/mL. Viral blips were defined as a transient HIV-RNA level >50 copies/mL preceded and followed by viral loads <50 copies/mL without any treatment change. Genotypic resistance testing and measurement of atazanavir plasma levels through a validated HPLC method18 were performed on plasma samples at the time of virological failure. The evaluation of the proportion of patients without treatment failure at week 96 was a secondary study endpoint. Analysis of the efficacy endpoint was performed both on the ITT exposed (ITT-e) population and the PP population. In addition, FDA snapshot analyses of treatment efficacy (success = any patient in study with an HIV-RNA <50 copies/mL in the time window ± 4 weeks) were carried out at 96 weeks in both the ITT-e and PP populations. The non-inferiority margin for the comparison of atazanavir/ritonavir + lamivudine versus atazanavir/ritonavir + 2NRTI was set at −12%. Superiority was assessed post hoc. Other secondary endpoints included the development of virological failure and drug resistance, occurrence of clinical and laboratory adverse events, changes in CD4 cell count, HIV-DNA, blood lipid levels and renal function, and self-reported adherence from baseline to week 96. Ethics The protocol was approved by the Ethics Committees of each participating centre and all procedures were performed in accordance with the Declaration of Helsinki. Patients provided written informed consent to study participation before enrolment. The study was registered with ClinicalTrials.gov, number NCT01599364. Statistical analysis Descriptive statistics were used to describe the baseline characteristics of patients. Categorical variables were compared using the χ2 test or Fisher’s exact test, as appropriate. Continuous variables were compared using the Student’s t-test or the Mann–Whitney U-test if they were normally or non-normally distributed, respectively. Only P values ≤0.05 were considered to be significant. All analyses were performed using the SPSS version 18.0 software package (SPSS Inc., Chicago, IL, USA). Results Patient characteristics Overall, 275 patients were screened for study participation and 266 patients were randomized, 133 to each study arm. Patient disposition at 96 weeks is illustrated in Figure 1. Baseline patients’ characteristics have been described previously.8 Briefly, 79.7% (n = 212) of patients were male with a median age of 44 years (IQR 36–50); 10.5% (n = 28) were HCV coinfected and 12.8% (n = 34) reported a previous AIDS-defining event. At baseline, patients had HIV-RNA <50 copies/mL from a median of 22.0 months (IQR 12.6–45.0) with a median CD4 count of 617 cells/mm3 (IQR 481–781). Before baseline, the NRTI backbone included tenofovir disoproxil fumarate in the majority of patients [n = 217 (81.6%)]. At baseline, the two arms were well balanced for the main characteristics (Table 1). Table 1. Baseline patient characteristics Total population, N = 266 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 Age (years)* 44 (36–50) 44 (36–49) 44 (36–51) Male 212 (79.7) 112 (84.2) 100 (75.2) Race  Caucasian 248 (93.2) 125 (94.0) 123 (92.5)  black 12 (4.5) 5 (3.8) 7 (5.3)  Latin American 5 (1.9) 2 (1.5) 3 (2.3)  other 1 (0.4) 1 (0.8) 0 (0.0) Risk factor  heterosexual 108 (40.6) 48 (36.1) 60 (45.1)  homo/bisexual 116 (43.6) 64 (48.1) 52 (39.1)  IVDU 20 (7.5) 9 (6.8) 11 (8.3)  other/unknown 22 (8.3) 12 (9.0) 10 (7.5) HCV coinfection 28 (10.5) 14 (10.5) 14 (10.5) Previous AIDS events 34 (12.8) 18 (13.5) 16 (12.0) Years from HIV diagnosis* 4.5 (2.2–9.5) 4.2 (2.2–9.0) 5.2 (2.6–10.3) Years from first ART initiation* 2.7 (1.6–5.5) 2.8 (1.7–5.1) 2.7 (1.6–6.4) ART line* 2 (1–3) 2 (1–3) 2 (1–3) Months from last regimen initiation* 29.1 (17.1–53.0) 28.7 (17.9–52.9) 29.2 (16.2–54.6) NRTI backbone  TDF+FTC/3TC 217 (81.6) 105a (78.9) 112a (84.2)  ABC+3TC 43 (16.2) 25 (18.8) 18 (13.5)  other 6 (2.3) 3b (2.3) 3c (2.3) Nadir CD4 count (cells/mm3)* 265 (132–357) 274 (118–357) 257 (144–357) Current CD4 count (cells/mm3)* 617 (481–781) 622 (472–779) 616 (486–783) Months from last HIV-1-RNA >50 copies/mL* 22.0 (12.6–45.0) 23.5 (12.6–46.5) 20.8 (12.3–44.8) Total population, N = 266 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 Age (years)* 44 (36–50) 44 (36–49) 44 (36–51) Male 212 (79.7) 112 (84.2) 100 (75.2) Race  Caucasian 248 (93.2) 125 (94.0) 123 (92.5)  black 12 (4.5) 5 (3.8) 7 (5.3)  Latin American 5 (1.9) 2 (1.5) 3 (2.3)  other 1 (0.4) 1 (0.8) 0 (0.0) Risk factor  heterosexual 108 (40.6) 48 (36.1) 60 (45.1)  homo/bisexual 116 (43.6) 64 (48.1) 52 (39.1)  IVDU 20 (7.5) 9 (6.8) 11 (8.3)  other/unknown 22 (8.3) 12 (9.0) 10 (7.5) HCV coinfection 28 (10.5) 14 (10.5) 14 (10.5) Previous AIDS events 34 (12.8) 18 (13.5) 16 (12.0) Years from HIV diagnosis* 4.5 (2.2–9.5) 4.2 (2.2–9.0) 5.2 (2.6–10.3) Years from first ART initiation* 2.7 (1.6–5.5) 2.8 (1.7–5.1) 2.7 (1.6–6.4) ART line* 2 (1–3) 2 (1–3) 2 (1–3) Months from last regimen initiation* 29.1 (17.1–53.0) 28.7 (17.9–52.9) 29.2 (16.2–54.6) NRTI backbone  TDF+FTC/3TC 217 (81.6) 105a (78.9) 112a (84.2)  ABC+3TC 43 (16.2) 25 (18.8) 18 (13.5)  other 6 (2.3) 3b (2.3) 3c (2.3) Nadir CD4 count (cells/mm3)* 265 (132–357) 274 (118–357) 257 (144–357) Current CD4 count (cells/mm3)* 617 (481–781) 622 (472–779) 616 (486–783) Months from last HIV-1-RNA >50 copies/mL* 22.0 (12.6–45.0) 23.5 (12.6–46.5) 20.8 (12.3–44.8) ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; ABC, abacavir. Values are expressed as n (%) except for *median (IQR). a One patient in each arm treated with TDF + 3TC and all others with TDF + FTC. b Two patients treated with zidovudine + 3TC and one patient treated with didanosine + 3TC. c One patient treated with zidovudine + 3TC, one patient treated with TDF + ABC and one patient treated with no NRTI backbone (treated with atazanavir/ritonavir + raltegravir, major protocol deviation). Table 1. Baseline patient characteristics Total population, N = 266 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 Age (years)* 44 (36–50) 44 (36–49) 44 (36–51) Male 212 (79.7) 112 (84.2) 100 (75.2) Race  Caucasian 248 (93.2) 125 (94.0) 123 (92.5)  black 12 (4.5) 5 (3.8) 7 (5.3)  Latin American 5 (1.9) 2 (1.5) 3 (2.3)  other 1 (0.4) 1 (0.8) 0 (0.0) Risk factor  heterosexual 108 (40.6) 48 (36.1) 60 (45.1)  homo/bisexual 116 (43.6) 64 (48.1) 52 (39.1)  IVDU 20 (7.5) 9 (6.8) 11 (8.3)  other/unknown 22 (8.3) 12 (9.0) 10 (7.5) HCV coinfection 28 (10.5) 14 (10.5) 14 (10.5) Previous AIDS events 34 (12.8) 18 (13.5) 16 (12.0) Years from HIV diagnosis* 4.5 (2.2–9.5) 4.2 (2.2–9.0) 5.2 (2.6–10.3) Years from first ART initiation* 2.7 (1.6–5.5) 2.8 (1.7–5.1) 2.7 (1.6–6.4) ART line* 2 (1–3) 2 (1–3) 2 (1–3) Months from last regimen initiation* 29.1 (17.1–53.0) 28.7 (17.9–52.9) 29.2 (16.2–54.6) NRTI backbone  TDF+FTC/3TC 217 (81.6) 105a (78.9) 112a (84.2)  ABC+3TC 43 (16.2) 25 (18.8) 18 (13.5)  other 6 (2.3) 3b (2.3) 3c (2.3) Nadir CD4 count (cells/mm3)* 265 (132–357) 274 (118–357) 257 (144–357) Current CD4 count (cells/mm3)* 617 (481–781) 622 (472–779) 616 (486–783) Months from last HIV-1-RNA >50 copies/mL* 22.0 (12.6–45.0) 23.5 (12.6–46.5) 20.8 (12.3–44.8) Total population, N = 266 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 Age (years)* 44 (36–50) 44 (36–49) 44 (36–51) Male 212 (79.7) 112 (84.2) 100 (75.2) Race  Caucasian 248 (93.2) 125 (94.0) 123 (92.5)  black 12 (4.5) 5 (3.8) 7 (5.3)  Latin American 5 (1.9) 2 (1.5) 3 (2.3)  other 1 (0.4) 1 (0.8) 0 (0.0) Risk factor  heterosexual 108 (40.6) 48 (36.1) 60 (45.1)  homo/bisexual 116 (43.6) 64 (48.1) 52 (39.1)  IVDU 20 (7.5) 9 (6.8) 11 (8.3)  other/unknown 22 (8.3) 12 (9.0) 10 (7.5) HCV coinfection 28 (10.5) 14 (10.5) 14 (10.5) Previous AIDS events 34 (12.8) 18 (13.5) 16 (12.0) Years from HIV diagnosis* 4.5 (2.2–9.5) 4.2 (2.2–9.0) 5.2 (2.6–10.3) Years from first ART initiation* 2.7 (1.6–5.5) 2.8 (1.7–5.1) 2.7 (1.6–6.4) ART line* 2 (1–3) 2 (1–3) 2 (1–3) Months from last regimen initiation* 29.1 (17.1–53.0) 28.7 (17.9–52.9) 29.2 (16.2–54.6) NRTI backbone  TDF+FTC/3TC 217 (81.6) 105a (78.9) 112a (84.2)  ABC+3TC 43 (16.2) 25 (18.8) 18 (13.5)  other 6 (2.3) 3b (2.3) 3c (2.3) Nadir CD4 count (cells/mm3)* 265 (132–357) 274 (118–357) 257 (144–357) Current CD4 count (cells/mm3)* 617 (481–781) 622 (472–779) 616 (486–783) Months from last HIV-1-RNA >50 copies/mL* 22.0 (12.6–45.0) 23.5 (12.6–46.5) 20.8 (12.3–44.8) ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; ABC, abacavir. Values are expressed as n (%) except for *median (IQR). a One patient in each arm treated with TDF + 3TC and all others with TDF + FTC. b Two patients treated with zidovudine + 3TC and one patient treated with didanosine + 3TC. c One patient treated with zidovudine + 3TC, one patient treated with TDF + ABC and one patient treated with no NRTI backbone (treated with atazanavir/ritonavir + raltegravir, major protocol deviation). Figure 1. View largeDownload slide Flow chart showing patient allocation throughout the study and main study outcomes. ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; RAL, raltegravir. Figure 1. View largeDownload slide Flow chart showing patient allocation throughout the study and main study outcomes. ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; RAL, raltegravir. Efficacy analysis At 96 weeks, in the ITT-e population, patients free of treatment failure numbered 103/133 (77.4%, 95% CI 70.3/84.5) in the atazanavir/ritonavir + lamivudine arm and 87/133 (65.4%, 95% CI 57.3/73.5) in the atazanavir/ritonavir + 2NRTI arm (difference atazanavir/ritonavir + lamivudine minus atazanavir/ritonavir + 2NRTI +12.0%, 95% CI +1.2/+22.8, P = 0.030) (Figure 2). Figure 2. View largeDownload slide Proportion of patients without treatment failure at week 96 (bottom) and differences between the two arms (top). ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; S = F, switch equal to failure. Figure 2. View largeDownload slide Proportion of patients without treatment failure at week 96 (bottom) and differences between the two arms (top). ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; S = F, switch equal to failure. Similar results were observed in the PP population: 102/131 (77.9%, 95% CI 70.8/85.0) patients in the atazanavir/ritonavir + lamivudine arm compared with 84/129 (65.1%, 95% CI 56.9/73.3) patients in the atazanavir/ritonavir + 2NRTI arm were free of treatment failure (difference between arms +12.8%, 95% CI +1.9%/+23.7%, P = 0.023). These results fulfil the predefined non-inferiority criteria and indicate superior efficacy of switching to atazanavir/ritonavir + lamivudine over continuing atazanavir/ritonavir + 2NRTI. The 96 week snapshot analysis also confirmed the superiority of switching to atazanavir/ritonavir + lamivudine. In the ITT-e population, 103/133 patients (77.4%, 95% CI 70.3/84.5) in the atazanavir/ritonavir + lamivudine arm versus 85/133 in the atazanavir/ritonavir + 2NRTI arm (63.9%, 95% CI 55.7/72.1) achieved treatment success (difference between arms +13.5%, 95% CI +2.7/+24.3, P = 0.015). In the PP population, treatment success was achieved in 102/131 patients (77.9%, 95% CI 70.8/85.0) in the atazanavir/ritonavir + lamivudine arm versus 82/129 in the atazanavir/ritonavir + 2NRTI arm (63.6%, 95% CI 55.3/71.9) (difference between arms +14.3%, 95% CI +3.4/+25.2, P = 0.011) (Figure 2). Detailed causes of treatment failure are reported in Table 2. As reported, during the first 48 weeks, there were two and six virological failures in the atazanavir/ritonavir + lamivudine arm and the atazanavir/ritonavir + 2NRTI arm, respectively;8 between weeks 49 and 96, three additional virological failures were observed with atazanavir/ritonavir + 2NRTI and none with atazanavir/ritonavir + lamivudine. Therefore, at week 96 there were more virological failures in the triple therapy arm [n = 9 (6.8%)] compared with the dual therapy arm [n = 2 (1.5%), P = 0.060] (see Table S1, available as Supplementary data at JAC Online, for details). Nine of 11 (81.8%) virological failures were successfully genotyped, both failures of the atazanavir/ritonavir + lamivudine arm and 7/9 of the atazanavir/ritonavir + 2NRTI arm: no significant resistance to any of the ongoing drugs was detected. Plasma samples for measurement of atazanavir levels at failure were available in 9/11 patients (2/2 in atazanavir/ritonavir + lamivudine and 7/9 in the atazanavir/ritonavir + 2NRTI). Undetectable atazanavir levels (<0.05 mg/L) were found in 1/2 (50%) and 3/7 (42.9%) plasma samples in the dual-therapy arm and the triple-therapy arm, respectively; in the remaining patients, the atazanavir concentration was above the suggested mid-dosing interval or trough concentration efficacy cut-off.19,20 Patients showing viral blips not leading to virological failure or treatment discontinuation were less frequently found in the dual-therapy arm, but the difference with the comparator arm was not statistically significant [n = 11 (8.3%) in the atazanavir/ritonavir + lamivudine arm and n = 20 (15.0%) in the atazanavir/ritonavir + 2NRTI arm, P = 0.085]. Table 2. Causes of treatment failure after 96 weeks ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P Any cause 30 (22.6) 46 (34.6) 0.030 Virological failure 2 (1.5) 9 (6.8) 0.060 Adverse events (potentially treatment related) 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow-up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P Any cause 30 (22.6) 46 (34.6) 0.030 Virological failure 2 (1.5) 9 (6.8) 0.060 Adverse events (potentially treatment related) 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow-up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n (%). Values in bold are statistically significant. Table 2. Causes of treatment failure after 96 weeks ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P Any cause 30 (22.6) 46 (34.6) 0.030 Virological failure 2 (1.5) 9 (6.8) 0.060 Adverse events (potentially treatment related) 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow-up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P Any cause 30 (22.6) 46 (34.6) 0.030 Virological failure 2 (1.5) 9 (6.8) 0.060 Adverse events (potentially treatment related) 7 (5.3) 11 (8.3) 0.329 Adverse events (not treatment related) 3 (2.3) 5 (3.8) 0.722 Withdrawal of consent 6 (4.5) 9 (6.8) 0.425 Loss to follow-up 10 (7.5) 7 (5.3) 0.452 Other 2 (1.5) 5 (3.8) 0.447 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n (%). Values in bold are statistically significant. The proportion of treatment failure due to potentially treatment-related or not-treatment-related adverse events was similar in both arms. HIV-DNA levels To monitor changes in the magnitude of the HIV-1 cellular reservoir, blood-associated HIV-DNA levels were quantified both at baseline and at week 96 in a subset of 140 patients. Mean baseline HIV-DNA levels (log10 copies/106 leucocytes) were comparable in the atazanavir/ritonavir + lamivudine arm (2.42, 95% CI 2.32/2.54) and the atazanavir/ritonavir + 2NRTI arm (2.37, 95% CI 2.24/2.51) (P = 0.570). Outcomes at 48 weeks have been presented elsewhere.21 At 96 weeks, a significant decrease from baseline in HIV-DNA (log10 copies/106 leucocytes) was observed in both arms: −0.15 (95% CI −0.23/−0.07, P < 0.001) in the dual-therapy arm versus −0.18 (95% CI −0.27/−0.08, P < 0.001) in the control arm, without significant differences between the two arms (P = 0.703). Clinical adverse events The proportion of patients with at least one clinical adverse event of any grade did not differ between arms and there were no significant differences regarding the types of events, although the atazanavir/ritonavir + 2NRTI arm tended to show a higher number of renal adverse events (Table 3). Most adverse events were mild to moderate. Table 3. Proportion of patients with clinical adverse events of any grade during 96 week follow-up ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P CNS 4 (3.0) 6 (4.5) 0.749 Gastrointestinal 13 (9.8) 10 (7.5) 0.513 Skin and soft tissues 7 (5.3) 1 (0.8) 0.066 Urinary tract 7 (5.3) 12 (9.0) 0.234 Respiratory tract 10 (7.5) 9 (6.8) 0.812 Infections 22 (16.5) 26 (19.5) 0.524 Neoplasm 5 (3.8) 3 (2.3) 0.722 Bone 6 (4.5) 9 (6.8) 0.425 Other 21 (15.8) 22 (16.5) 0.868 Patients with at least one adverse event 52 (39.1) 52 (39.1) 1.000 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P CNS 4 (3.0) 6 (4.5) 0.749 Gastrointestinal 13 (9.8) 10 (7.5) 0.513 Skin and soft tissues 7 (5.3) 1 (0.8) 0.066 Urinary tract 7 (5.3) 12 (9.0) 0.234 Respiratory tract 10 (7.5) 9 (6.8) 0.812 Infections 22 (16.5) 26 (19.5) 0.524 Neoplasm 5 (3.8) 3 (2.3) 0.722 Bone 6 (4.5) 9 (6.8) 0.425 Other 21 (15.8) 22 (16.5) 0.868 Patients with at least one adverse event 52 (39.1) 52 (39.1) 1.000 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n (%). Grade 3–4 clinical adverse events: nine in the dual-therapy arm [two sudden deaths (probably cardiac), thyroid carcinoma, melanoma, atrial fibrillation, bronchitis, asthma, biliary colic and pancreatitis; the last two events were considered treatment related] and nine in the triple-therapy arm (abdominal cancer, prostate adenocarcinoma, pneumonia, radiculitis, traumatic tibia fracture, finger amputation, pregnancy, cervicitis and renal colic; the last event was considered treatment related). Table 3. Proportion of patients with clinical adverse events of any grade during 96 week follow-up ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P CNS 4 (3.0) 6 (4.5) 0.749 Gastrointestinal 13 (9.8) 10 (7.5) 0.513 Skin and soft tissues 7 (5.3) 1 (0.8) 0.066 Urinary tract 7 (5.3) 12 (9.0) 0.234 Respiratory tract 10 (7.5) 9 (6.8) 0.812 Infections 22 (16.5) 26 (19.5) 0.524 Neoplasm 5 (3.8) 3 (2.3) 0.722 Bone 6 (4.5) 9 (6.8) 0.425 Other 21 (15.8) 22 (16.5) 0.868 Patients with at least one adverse event 52 (39.1) 52 (39.1) 1.000 ATV/RTV + 3TC, N = 133 ATV/RTV + 2NRTI, N = 133 P CNS 4 (3.0) 6 (4.5) 0.749 Gastrointestinal 13 (9.8) 10 (7.5) 0.513 Skin and soft tissues 7 (5.3) 1 (0.8) 0.066 Urinary tract 7 (5.3) 12 (9.0) 0.234 Respiratory tract 10 (7.5) 9 (6.8) 0.812 Infections 22 (16.5) 26 (19.5) 0.524 Neoplasm 5 (3.8) 3 (2.3) 0.722 Bone 6 (4.5) 9 (6.8) 0.425 Other 21 (15.8) 22 (16.5) 0.868 Patients with at least one adverse event 52 (39.1) 52 (39.1) 1.000 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n (%). Grade 3–4 clinical adverse events: nine in the dual-therapy arm [two sudden deaths (probably cardiac), thyroid carcinoma, melanoma, atrial fibrillation, bronchitis, asthma, biliary colic and pancreatitis; the last two events were considered treatment related] and nine in the triple-therapy arm (abdominal cancer, prostate adenocarcinoma, pneumonia, radiculitis, traumatic tibia fracture, finger amputation, pregnancy, cervicitis and renal colic; the last event was considered treatment related). There were 18 grade 3 or 4 clinical adverse events: 9 per arm, but only 3 were considered treatment related (see Table 3 footnotes for details). Two sudden deaths, probably from cardiac disease, occurred in the atazanavir/ritonavir + lamivudine arm, both were not considered treatment related. Two malignant cancers were diagnosed during the study in each study arm (thyroid carcinoma and melanoma in the atazanavir/ritonavir + lamivudine arm; abdominal cancer and prostate adenocarcinoma in the atazanavir/ritonavir + 2NRTI arm). Overall, eight renal colics occurred during 96 weeks (two in the atazanavir/ritonavir + lamivudine arm and six in the atazanavir/ritonavir + 2NRTI arm); these led to treatment discontinuation in five cases (two in the atazanavir/ritonavir + lamivudine arm and three in the atazanavir/ritonavir + 2NRTI arm). Laboratory toxicity and evolution of laboratory parameters A significantly higher number of patients randomized to atazanavir/ritonavir + lamivudine showed at least one grade 3 or 4 laboratory adverse event (79.9% versus 67.7% in the triple-therapy arm, P = 0.026) (Table 4). This excess was mainly attributable to a higher frequency of hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) in the dual-therapy arm. However, no patient discontinued the regimen for grade 3 or 4 laboratory adverse events. Indeed, grade 1 or 2 laboratory adverse events led to treatment discontinuation in two (1.5%) patients in the atazanavir/ritonavir + lamivudine arm (one grade 2 hypertriglyceridaemia, one grade 1 creatinine increase) and five (3.8%) patients in the atazanavir/ritonavir + 2NRTI arm (one grade 2 hyperbilirubinemia, three grade 1 creatinine increase and one grade 1 proteinuria) (P = 0.447). Table 4. Proportion of patients with grade 3–4 laboratory toxicities Total grade 3–4 toxicities Newa grade 3–4 toxicities ATV/RTV + 3TC ATV/RTV + 2NRTI P ATV/RTV + 3TC ATV/RTV + 2NRTI P Total cholesterol 8/133 (6.0) 4/133 (3.0) 0.237 6/126 (4.8) 2/126 (1.6) 0.281 LDL cholesterol 19/133 (14.3) 11/133 (8.3) 0.121 12/111 (10.8) 7/115 (6.1) 0.201 Triglycerides 9/133 (6.8) 2/133 (1.5) 0.031 9/126 (7.1) 2/128 (1.6) 0.029 Total bilirubin 89/133 (66.9) 67/133 (50.4) 0.006 59/99 (59.6) 37/99 (37.4) 0.002 ALT 0/133 (0) 2/133 (1.5) 0.156 0/129 (0) 1/128 (0.8) 0.314 At least one laboratory toxicity 106/133 (79.7) 90/133 (67.7) 0.026 76/133 (57.1) 57/133 (42.9) 0.027 Total grade 3–4 toxicities Newa grade 3–4 toxicities ATV/RTV + 3TC ATV/RTV + 2NRTI P ATV/RTV + 3TC ATV/RTV + 2NRTI P Total cholesterol 8/133 (6.0) 4/133 (3.0) 0.237 6/126 (4.8) 2/126 (1.6) 0.281 LDL cholesterol 19/133 (14.3) 11/133 (8.3) 0.121 12/111 (10.8) 7/115 (6.1) 0.201 Triglycerides 9/133 (6.8) 2/133 (1.5) 0.031 9/126 (7.1) 2/128 (1.6) 0.029 Total bilirubin 89/133 (66.9) 67/133 (50.4) 0.006 59/99 (59.6) 37/99 (37.4) 0.002 ALT 0/133 (0) 2/133 (1.5) 0.156 0/129 (0) 1/128 (0.8) 0.314 At least one laboratory toxicity 106/133 (79.7) 90/133 (67.7) 0.026 76/133 (57.1) 57/133 (42.9) 0.027 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n/N (%). Values in bold are statistically significant. a Incident toxicity, not present at baseline. Table 4. Proportion of patients with grade 3–4 laboratory toxicities Total grade 3–4 toxicities Newa grade 3–4 toxicities ATV/RTV + 3TC ATV/RTV + 2NRTI P ATV/RTV + 3TC ATV/RTV + 2NRTI P Total cholesterol 8/133 (6.0) 4/133 (3.0) 0.237 6/126 (4.8) 2/126 (1.6) 0.281 LDL cholesterol 19/133 (14.3) 11/133 (8.3) 0.121 12/111 (10.8) 7/115 (6.1) 0.201 Triglycerides 9/133 (6.8) 2/133 (1.5) 0.031 9/126 (7.1) 2/128 (1.6) 0.029 Total bilirubin 89/133 (66.9) 67/133 (50.4) 0.006 59/99 (59.6) 37/99 (37.4) 0.002 ALT 0/133 (0) 2/133 (1.5) 0.156 0/129 (0) 1/128 (0.8) 0.314 At least one laboratory toxicity 106/133 (79.7) 90/133 (67.7) 0.026 76/133 (57.1) 57/133 (42.9) 0.027 Total grade 3–4 toxicities Newa grade 3–4 toxicities ATV/RTV + 3TC ATV/RTV + 2NRTI P ATV/RTV + 3TC ATV/RTV + 2NRTI P Total cholesterol 8/133 (6.0) 4/133 (3.0) 0.237 6/126 (4.8) 2/126 (1.6) 0.281 LDL cholesterol 19/133 (14.3) 11/133 (8.3) 0.121 12/111 (10.8) 7/115 (6.1) 0.201 Triglycerides 9/133 (6.8) 2/133 (1.5) 0.031 9/126 (7.1) 2/128 (1.6) 0.029 Total bilirubin 89/133 (66.9) 67/133 (50.4) 0.006 59/99 (59.6) 37/99 (37.4) 0.002 ALT 0/133 (0) 2/133 (1.5) 0.156 0/129 (0) 1/128 (0.8) 0.314 At least one laboratory toxicity 106/133 (79.7) 90/133 (67.7) 0.026 76/133 (57.1) 57/133 (42.9) 0.027 ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine. Values are expressed as n/N (%). Values in bold are statistically significant. a Incident toxicity, not present at baseline. The evolution of CD4 and serum biochemical parameters from baseline to 96 weeks is illustrated in Figure 3. Mean changes in CD4 count did not differ between arms (+77 cells/mm3 with atazanavir/ritonavir + lamivudine versus +49 cells/mm3 with atazanavir/ritonavir + 2NRTI, P = 0.306). Mean changes in total cholesterol levels were +16 mg/dL in the atazanavir/ritonavir + lamivudine arm and +0 mg/dL in the atazanavir/ritonavir + 2NRTI arm (P = 0.002), with a concomitant increase in LDL cholesterol (+13 mg/dL with atazanavir/ritonavir + lamivudine versus +4 mg/dL with atazanavir/ritonavir + 2NRTI, P = 0.092) and HDL cholesterol (+5 mg/dL with atazanavir/ritonavir + lamivudine versus +0 mg/dL with atazanavir/ritonavir + 2NRTI, P = 0.002); as a result, modifications of total/HDL cholesterol (+3.1 versus +0.7, P = 0.361) and HDL/LDL cholesterol (0 versus −0.1, P = 0.730) ratios from baseline to 96 weeks did not differ between arms. At 96 weeks, renal function showed a significant improvement in the atazanavir/ritonavir + lamivudine versus the atazanavir/ritonavir + 2NRTI arm with a mean change from baseline eGFRMDRD of +5 mL/min/1.73 m2 versus −2 mL/min/1.73 m2, respectively (P < 0.001) (where eGFR stands for estimated glomerular filtration rate and MDRD stands for Modification of Diet in Renal Disease Study Equation). Conversely, a slight increase in total bilirubin levels was observed in the dual-therapy arm (+0.2 versus −0.1 mg/dL, P = 0.039). Figure 3. View largeDownload slide Mean change from baseline values at week 96 in (a) peripheral blood CD4 T cell counts, (b) blood lipids, (c) eGFR and (d) bilirubin values in the two treatment arms. ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TC, total cholesterol; LDL, LDL cholesterol; HDL, HDL cholesterol; TG, triglyceride; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration formula; MDRD, Modification of Diet in Renal Disease Study Equation. Figure 3. View largeDownload slide Mean change from baseline values at week 96 in (a) peripheral blood CD4 T cell counts, (b) blood lipids, (c) eGFR and (d) bilirubin values in the two treatment arms. ATV, atazanavir; RTV, ritonavir; 3TC, lamivudine; TC, total cholesterol; LDL, LDL cholesterol; HDL, HDL cholesterol; TG, triglyceride; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration formula; MDRD, Modification of Diet in Renal Disease Study Equation. Neurocognitive performance Neurocognitive data at 96 weeks were available for 107 patients (40.2% on the total), 56 in the study arm and 51 in the control arm. At baseline, patients in the two arms did not differ in terms of their main characteristics (data not shown) and showed a comparable proportion of cognitive impairment (10.7% in the atazanavir/ritonavir + lamivudine arm versus 21.7% in the atazanavir/ritonavir + 2NRTI arm, all with a profile of asymptomatic cognitive impairment,16P = 0.185). At 96 weeks, the two groups confirmed no difference in the prevalence of cognitive impairment (14.3% versus 13.7%, respectively, P = 1.000). Analysing each arm separately, both groups confirmed no change in the prevalence of cognitive impairment at 96 weeks in comparison with baseline (atazanavir/ritonavir + lamivudine arm: 14.3% versus 10.7%, P = 0.625; atazanavir/ritonavir + 2NRTI arm: 13.7% versus 21.7%, P = 0.219). Bone health and body fat distribution Bone mineral density, body fat distribution (as measured by DEXA scan) and biomarkers of bone metabolism were available at baseline and 96 weeks for 91 (34.2%) patients (52 in the atazanavir/ritonavir + lamivudine arm and 39 in the atazanavir/ritonavir + 2NRTI arm). At baseline, bone loss at any site (in terms of osteopenia or osteoporosis) was diagnosed in 61.5% (n = 56) of patients, of which 34/52 (65.4%) were in the atazanavir/ritonavir + lamivudine arm and 22/39 (56.4%) were in the atazanavir/ritonavir + 2NRTI arm (P = 0.384). At 96 weeks, we observed a significantly higher increase in lumbar spine bone mineral density in dual therapy (mean change versus baseline +4.2% versus −2.5% in the triple-therapy arm, P = 0.021), with no differences in total hip and femoral neck bone mineral density between arms (Table S2). Evaluating bone biomarkers, a significant reduction in parathyroid hormone levels was observed in the atazanavir/ritonavir + lamivudine arm (−9.4 versus +0.9 pg/mL in the atazanavir/ritonavir + 2NRTI arm, P = 0.008); no significant between-arm differences were observed for the other bone biomarkers. Exploring body fat distribution, at 96 weeks no significant differences between the two arms were observed in terms of change in limb or trunk fat and lean mass (Table S2). Adherence During the study, adherence data were provided by 254 (95.5%) patients [130 (97.7%) in the atazanavir/ritonavir + lamivudine arm and 124 (93.2%) in the atazanavir/ritonavir + 2NRTI arm, P = 0.137]. At baseline, adherence was similar in the two arms [mean: 86% (SD 18) in the atazanavir/ritonavir + lamivudine arm and 88% (SD 14) in the atazanavir/ritonavir + 2NRTI arm, P = 0.306]. During the entire follow-up, no significant differences were observed in terms of adherence levels at any study visit [mean change versus baseline at 96 weeks: +2% (SD 18) in the atazanavir/ritonavir + lamivudine arm and −1% (SD 15) in the atazanavir/ritonavir + 2NRTI arm, P = 0.312]. Discussion Studies investigating a treatment switch to dual therapy with a boosted PI plus lamivudine in virologically suppressed HIV-infected patients have shown promising results,5,8,9 but few data are available about the efficacy of this strategy over the long term.7,10 Moreover, real benefits in terms of reduced toxicity have not been completely demonstrated and concerns remain about reduced activity in sanctuary sites (e.g. the CNS). At 96 weeks, the results of the ATLAS-M trial confirm the non-inferiority of treatment simplification to atazanavir/ritonavir + lamivudine versus continuing an atazanavir/ritonavir-based triple therapy in virologically suppressed patients. Moreover, a post hoc superiority of this dual therapy was demonstrated by all types of analyses performed. This result was driven by several factors, including lower discontinuation rates for adverse events (both treatment and not treatment related), less frequent withdrawal of consent but also, most importantly, by lower rates of virological failure in the atazanavir/ritonavir + lamivudine arm. Only two virological failures (one of which occurred at baseline before the treatment switch) were observed with the dual therapy during the first 48 weeks and no further virological failure occurred thereafter. Moreover, no emerging HIV-1 drug resistance was observed at failure in both arms. These results confirm the efficacy over the long term of treatment simplification to atazanavir/ritonavir + lamivudine in virologically suppressed patients with very low risk of virological failure and absence of resistance in the case of failure. Regarding tolerability, patients switched to atazanavir/ritonavir + lamivudine showed a significant recovery of eGFR when compared with those continuing triple therapy, suggesting that this regimen could halt the deterioration of renal function. This observation can be ascribed to the discontinuation of tenofovir disoproxil fumarate in the majority of patients randomized to the dual-therapy arm. Whether a similar result could be obtained with a switch to a tenofovir alafenamide-containing backbone remains to be determined as no studies have yet directly compared tenofovir alafenamide with dual therapies.22 The discontinuation of tenofovir disoproxil fumarate could also explain the improvements in lumbar spine bone mineral density23 observed in the atazanavir/ritonavir + lamivudine arm, while patients treated with atazanavir/ritonavir + 2NRTI worsened; as expected after tenofovir disoproxil fumarate discontinuation,24 we also observed a reduction in parathyroid hormone levels in the dual-therapy arm, which might have been translated into a lower bone resorption. Patients switched to dual therapy showed a slight increase in total cholesterol but also HDL cholesterol; this can be ascribed to the discontinuation of tenofovir disoproxil fumarate, which has a known lipid-lowering effect.25,26 However, total/HDL cholesterol and HDL/LDL cholesterol ratios remained unchanged and, as a consequence, the impact on the cardiovascular risk is expected to be negligible. In the dual-therapy arm, we observed a higher proportion of patients developing grade 3 or 4 increases in bilirubin and triglyceride levels, but this did not impact the tolerability of the regimens since treatment discontinuations for laboratory adverse events were similar between arms. A potential explanation for higher bilirubin levels in the dual-therapy arm could be an increase in atazanavir plasma concentration due to tenofovir disoproxil fumarate discontinuation, which occurred in the majority of patients, as suggested by drug–drug interaction studies.27 A supposed drawback of dual therapy is potential concern about reduced efficacy in controlling viral replication in sanctuary sites. To assess this issue in ATLAS-M, total HIV-DNA level, a surrogate marker of viral replication in reservoirs,28 was measured during the study. At 96 weeks, we observed a significant decrease in total HIV-DNA levels in both arms, without any significant between-arm differences. This observation confirms results obtained at 48 weeks21 and offers a degree of reassurance about the ability of this dual regimen in controlling viral replication in reservoirs over the long term. Another concern about simplification to dual therapies is the potential for inadequate drug activity in the CNS. Importantly, in our study no significant difference in the prevalence of neurocognitive impairment was observed between the two study arms at 96 weeks, suggesting a CNS-safe profile of simplification to atazanavir/ritonavir + lamivudine, at least in the medium term, in subjects with stable plasma viral load control and without symptomatic neurocognitive impairment. Treatment simplification to atazanavir/ritonavir + lamivudine in virologically suppressed patients has also been investigated by the SALT trial, which demonstrated non-inferior efficacy (although not superiority) at 96 weeks of the dual therapy over an atazanavir/ritonavir-based triple therapy, without any benefit in terms of tolerability.10 The SALT and ATLAS-M trials were slightly different regarding study design and this could explain why superior efficacy and better renal tolerability of atazanavir/ritonavir + lamivudine were not shown in the SALT trial. The SALT trial enrolled patients on any ART regimen and allowed switching of the NRTI backbone at baseline in those with tolerability issues, thus efficacy results relied also on tolerability of drugs not previously taken by patients. In the ATLAS-M trial, all patients were treated with atazanavir/ritonavir + 2NRTI before baseline, and therefore those randomized to dual therapy simply removed an NRTI from their standard triple-therapy regimen. In this way, the study design of the ATLAS-M trial more accurately reflects what happens when an NRTI drug is removed from a standard triple-therapy regimen, both in terms of efficacy and tolerability. Some limitations should be acknowledged when interpreting the results of our study. Since this is an open-label study, physicians could have been more prone to discontinue treatment if toxicity occurred and this could have partly influenced the main outcome. However, this potential bias does not influence virological outcome, which was favourable with dual therapy. It should also be emphasized that patients included in the ATLAS-M study were accurately selected according to strict inclusion and exclusion criteria, meaning that results cannot be generalized to all HIV-infected patients. In particular, this dual regimen should not be prescribed to patients without stable virological suppression, with a low CD4 count, with previous episodes of virological failure or with coinfection with HBV, as for all other tenofovir-sparing regimens. In conclusion, in the ATLAS-M trial, the safety and efficacy of treatment simplification to atazanavir/ritonavir + lamivudine in virologically suppressed patients were confirmed over 96 weeks, with a post hoc superiority of dual therapy over a standard triple-therapy regimen. A sustained benefit in terms of preserved renal function and improvement in lumbar spine bone mineral density was observed, without other significant laboratory concerns. Of note, no concerns about the efficacy of dual therapy in sanctuary sites emerged during the 96 weeks of the trial, as demonstrated by the constant decrease in total blood HIV-DNA levels and by the evolution of cognitive performance. These promising efficacy and safety data of atazanavir/ritonavir + lamivudine, together with a potential for substantial cost reduction of ART,29,30 especially if generic drugs are used, make this regimen a suitable option for treatment simplification. Acknowledgements Preliminary data were presented at the HIV Drug Therapy Glasgow Congress 2016 (Abstract P086).  We would like to thank the ATLAS-M study participants for taking part in this trial, the ATLAS-M investigators and their staff for contributing to the realization of this study and the external contract research organization for its assistance during the study. Members of the ATLAS-M Study Group R. Cauda, S. Di Giambenedetto, M. Fabbiani, A. Mondi, N. Ciccarelli, A. Borghetti, E. Baldonero, S. Belmonti, A. D’Avino, R. Gagliardini, S. Lamonica, F. Lombardi, L. Sidella, E. Tamburrini, E. Visconti (Istituto di Clinica delle Malattie Infettive, Università Cattolica del S. Cuore Policlinico Universitario A. Gemelli); A. De Luca (Clinica di Malattie Infettive, Università degli Studi di Siena); A. Giacometti, F. Barchiesi, P. Castelli, O. Cirioni, S. Mazzocato (Struttura Organizzativa Dipartimentale Clinica di Malattie infettive, Azienda Ospedaliero Universitaria—Ospedali Riuniti di Ancona); M. Di Pietro, P. Blanc, A. Degli Esposti, B. Del Pin, E. Mariabelli, S. Marini, A. Poggi (UO Malattie Infettive, Ospedale S. M. Annunziata Firenze); E. Quiros Roldan, E. Focà, S. Amadasi, A. Apostoli, L. Biasi, A. Bonito, N. Brianese, S. Compostella, A. Ferraresi, D. Motta (Istituto di Malattie Infettive e Tropicali, Università di Brescia—Azienda Ospedaliera Spedali Civili, Brescia); M.T. Mughini, B.M. Celesia, M. Gussio, S. Sofia (Istituto Malattie Infettive, ARNAS Garibaldi PO Nesima); P. Grima, M. Tana, P. Tundo (UOC di Malattie Infettive, PO ‘S. Caterina Novella’); C. Viscoli, L. De Hoffer, A. Di Biagio, S. Grignolo, A. Parisini, E. Schenone, L. Taramasso (Clinica Malattie Infettive, Azienda Ospedaliera Universitaria San Martino Genova); P.E. Manconi, A. Boccone, F. Ortu, P. Piano, L. Serusi (Centro di Immunologia, AO Universitaria—Cagliari); M. Puoti, M. C. Moioli, R. Rossotti, G. Travi, F. Ventura (Istituto di Malattie Infettive, AO Ospedale Niguarda Cà Granda Milano); M. Galli, S. Rusconi, S. Di Nardo Stuppino, V. Di Cristo, A. Giacomelli, V. Vimercati (Dip. di Scienze Cliniche L. Sacco/Sez. Malattie Infettive, Ospedale Luigi Sacco di Milano Azienda ospedaliera e Polo Universitario); P. Viale (UO Malattie infettive, Policlinico S. Orsola Malpighi Bologna); A. Gori (UO Malattie infettive, Azienda Ospedaliera San Gerardo Monza); G. Rizzardini, A. Capetti, L. Carenzi, F. Mazza, P. Meraviglia, S. Rosa, P. Zucchi (Malattie infettive I Divisione, Ospedale Luigi Sacco di Milano); M. Mineo (Istituto di Malattie Infettive, AO Universitaria Policlinico Paolo Giaccone di Palermo); A. Latini, M. Colafigli, M. Giuliani, A. Pacifici, F. Pimpinelli, F. Solivetti, F. Stivali (UOC Dermatologia Infettiva, IRCCS Istituto Dermatologico S. Gallicano IFO); A. Antinori, F. Angelici, R. Bellagamba, D. Delle Rose, R. Fezza, R. Libertone, S. Mosti, P. Narciso, E. Nicastri, S. Ottou, C. Tomassi, C. Vlassi, M. Zaccarelli, F. Zoppè (UOC Malattie Infettive e Tropicali IV Divisione, INMIL Spallanzani IRCCS); V. Vullo, G. D’Ettorre, F. Altavilla, G. Ceccarelli, A. Fantauzzi, S. Gebremeskel, S. Lo Menzo, I. Mezzaroma, F. Tierno (Dipartimento di Malattie Infettive e Tropicali, Università degli studi di Roma La Sapienza); N. Petrosillo, P. Chinello, E. Boumis, S. Cicalini, E. Grilli, M. Musso, C. Stella (UOC Infezioni Sistemiche e dell'Immunodepresso II Divisione, INMIL Spallanzani IRCCS); M. S. Mura, G. Madeddu, P. Bagella, M. Mannazzu, V. Soddu (Reparto Malattie Infettive, Università degli studi di Sassari); P. Caramello, G. Orofino, C. Carcieri, S. Carosella, M. Farenga (Divisione A Malattie Infettive, Ospedale Amedeo di Savoia); P. G. Scotton, M. C. Rossi (UO Malattie infettive, Azienda ULSS 9 Treviso Ospedale S. Maria di Ca'Foncello); E. Concia, F. Corsini, C. Gricolo, M. Lanzafame, E. Lattuada, S. Leonardi, F. Rigo (UOC Malattie infettive, Azienda Ospedaliera Universitaria Integrata di Verona); A. Lazzarin, A. Castagna, A. Bigoloni, E. Carini, S. Nozza, V. Spagnuolo (Malattie infettive, Ospedale San Raffaele Milano); D. Francisci, B. Belfiori, L. Malincarne, E. Schiaroli, C. Sfara, A. Tosti (Clinica di Malattie Infettive, Ospedale S. Maria della Misericordia Perugia); D. Sacchini, A. Ruggieri, C. Valdatta (UO Malattie infettive—Dipartimento Medicina Specialistica, Ospedale Guglielmo Da Saliceto Ausl Di Piacenza). Funding This work was supported by Bristol-Myers Squibb, which provided an unrestricted grant to the Catholic University of Sacred Heart (the sponsor) and one of the study drugs (atazanavir) for the experimental arm. Transparency declarations M. F. has received speakers’ honoraria and support for travel to meetings from Bristol-Myers Squibb (BMS), Gilead, Merck Sharp & Dohme (MSD), ViiV Healthcare and Janssen-Cilag, and has received fees for attending advisory boards from BMS and Gilead. R. G. has received support for travel from Gilead and Janssen-Cilag. E. Q. R. has received grants from Gilead and ViiV, and has received personal fees from Gilead, BMS, MSD, Janssen-Cilag and ViiV. A. L. has received support for travel from Gilead, BMS and Janssen-Cilag. A. A. has received personal fees from BMS, Gilead, Merck, ViiV, AbbVie and Janssen-Cilag, and has received grants from BMS, Gilead, ViiV and Janssen-Cilag. G. O. has received personal fees from Gilead and ViiV. P. C. has received grants from Pfizer. S. R. has received personal fees from AbbVie, Gilead, ViiV, Janssen, BMS and MSD, and has received grants from Gilead, ViiV and Janssen-Cilag. A. D. has received travel grants from MSD, Gilead, BMS and ViiV Healthcare. E. F. has received personal fees from Gilead, BMS, MSD, Janssen-Cilag and ViiV, and has received grants from Gilead and ViiV. M. C. has received support for travel from Gilead, BMS and Janssen-Cilag. R. C. has been an advisor for Gilead, Janssen-Cilag and Basel Pharmaceutical, and has received speakers’ honoraria from ViiV, BMS, MSD, Abbott, Gilead and Janssen-Cilag. S. D. G. has received speakers’ honoraria and support for travel to meetings from Gilead, BMS, Abbott, Boehringer Ingelheim, Janssen-Cilag and GlaxoSmithKline. A. D. L. has received speaker’s honoraria and fees for attending advisory boards from ViiV, Gilead, AbbVie, Janssen-Cilag, MSD and BMS, and has received unrestricted research grants (to his institution) from ViiV Italy, Gilead Sciences (Fellowship Programme) and MSD Italy. All other authors: none to declare. Author contributions S. D. G., R. C. and A. D. L. designed the study, analysed the data and finalized the drafting of the paper. M. 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Update of the budget impact analysis of the simplification to atazanavir + ritonavir + lamivudine dual therapy of HIV-positive patients receiving atazanavir-based triple therapies in Italy starting from data of the Atlas-M trial . Clinicoecon Outcomes Res 2017 ; 9 : 569 – 71 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 12, 2018

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