Low-dose ritonavir-boosted darunavir in virologically suppressed HIV-1-infected adults: an open-label trial (ANRS 165 Darulight)

Low-dose ritonavir-boosted darunavir in virologically suppressed HIV-1-infected adults: an... Abstract Objectives To assess whether low-dose ritonavir-boosted darunavir (darunavir/r) in combination with two NRTIs could maintain virological suppression in patients on a standard regimen of darunavir/r + two NRTIs. Design A multicentre, Phase II, non-comparative, single-arm, open-label study. Setting Tertiary care hospitals in France. Subjects One hundred HIV-1-infected adults with no darunavir or NRTI resistance-associated mutations (RAMs) and a plasma HIV RNA level ≤50 copies/mL for ≥12 months on once-daily darunavir/r (800/100 mg) + two NRTIs for ≥6 months were switched to darunavir/r 400/100 mg with the same NRTIs. Primary outcome measure Proportion of patients with treatment success: plasma HIV RNA level ≤50  copies/mL up to 48 weeks without any change in the study regimen, in a modified ITT (mITT) analysis. Results At baseline, most patients were male (78%), with a median age of 43 years, median duration of HIV RNA ≤50 copies/mL of 35 months and median CD4 T cell count of 633 cells/mm3. Seventy-six percent received tenofovir/emtricitabine and 24% abacavir/lamivudine. Five patients were excluded from the mITT analysis. The rate of treatment success through to week 48 was 91.6% (87/95; 95% CI 84.1%–96.3%). No RAM was detected in three amplifiable genotypes. A total of 212 adverse events (AEs) occurred in 64 patients (64%); 9 AEs were serious, none leading to treatment discontinuation. Conclusions In HIV-infected patients well suppressed with darunavir/r (800/100 mg) and two NRTIs, a reduction of the darunavir dose to 400 mg/day maintained virological efficacy and was safe over 48 weeks. Introduction Continuous improvements in the treatment of HIV infection have led to high rates of sustained virological suppression and good tolerability, thereby reducing morbidity and mortality.1 However, because treatment is life-long, simplified regimens are needed to improve convenience and adherence, and to reduce drug-related adverse events (AEs) and cost.2–3 Among current strategies being assessed to improve antiretroviral therapies, such as co-formulation of multiple agents in a single pill and dual therapy or long-acting injectable agents, dose reduction of antiretroviral agents has been less frequently investigated.4–6 WHO has, however, recently updated its guidelines to recommend low-dose efavirenz (400 mg daily instead of 600 mg) as an alternative first-line regimen in low- and middle-income countries, following the results of a large randomized trial.7–9 PIs, despite a unique high genetic barrier to the development of resistance when boosted with low-dose ritonavir (r), have been moved to alternative or second-line regimens because of their imperfect tolerability profile and high cost.7–10 Pioneering studies that demonstrated that lower doses of ritonavir-boosted indinavir induced and maintained adequate virological suppression with improved safety and adequate PK established an interest in examining lowered doses of boosted PIs.11–13 Few studies thereafter have assessed the safety and efficacy of low-dose second-generation PIs in combination with other antiretroviral agents, which might improve tolerability and reduce costs.14–16 Once-daily ritonavir-boosted darunavir (darunavir/r) at the dose of 800/100 mg has demonstrated durable efficacy in both treatment-naive and treatment-experienced patients with no darunavir resistance-associated mutations (RAMs), and a better tolerability profile than ritonavir-boosted atazanavir.17–21 We wished to investigate a reduced dose of darunavir (400 mg) in combination with ritonavir in well-suppressed patients on the standard dose of once-daily darunavir/r + two NRTIs. Patients and methods Patient population Patients enrolled in the ANRS 165 Darulight study were treatment-experienced, HIV-1-infected adults (≥18 years), with a plasma HIV-1 RNA ≤50 copies/mL for at least 12 months, no previous virological failure, defined as a plasma HIV RNA >200 copies/mL, CD4 cell count >300 cells/mm3 and none of the 11 darunavir (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V) or NRTI RAMs detected by a resistance genotype test before treatment initiation.22 Patients needed to be receiving a stable darunavir-containing regimen for ≥6 months at screening with once-daily darunavir/r (800/100 mg) + two NRTIs [tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC)]. Patients with chronic hepatitis B and/or C infection were allowed to enrol if their condition was clinically stable and they were not expected to require treatment during the study period. Other exclusion criteria included HIV-2 infection, the presence of any active AIDS-defining illness, use of disallowed concomitant therapy, pregnancy/breastfeeding, and laboratory abnormalities (ALT or AST levels >2-fold the upper limit of normal, haemoglobin level <11 g/dL, platelet count <150 000/mm3), or estimated CLCR using the Cockroft–Gault equation <60 mL/min if tenofovir disoproxil fumarate was used. Study design ANRS 165 Darulight was a multicentre Phase II, non-comparative, single-arm, open-label study assessing the efficacy, safety and tolerability of switching from once-daily darunavir/r 800/100 mg + two NRTIs to once-daily darunavir/r 400/100 mg with the same two NRTIs, over 48 weeks in well-suppressed treatment-experienced patients with no darunavir or NRTI RAMs. Study treatments were delivered every 2 months at each hospital pharmacy site and patients received, in addition to their NRTI backbone (TDF/FTC or ABC/3TC), a bottle of 60 pills containing 400 mg of darunavir and 60 pills containing 100 mg of ritonavir. The study drugs had to be taken once daily with food to increase darunavir bioavailability.23 The trial consisted of a screening period (up to 4 weeks), a 48 week treatment period, and an extended follow-up of 24 weeks up to week 72 until the last participant completed the 48 week visit. The primary objective was to establish the proportion of patients with treatment success through to 48 weeks, defined as plasma HIV RNA levels ≤50 copies/mL without any change in the darunavir/r dose, in a modified ITT (mITT) analysis. The primary analysis was performed when all actively enrolled patients had completed 48 weeks. Written informed consent was obtained from all study participants. The study protocol was reviewed and approved by the Paris Saint-Louis ethics committee (Comité de Protection des Personnes) and health authority (EudraCT number 2014-001505-40), was conducted in accordance with good clinical practice and the Declaration of Helsinki, and was registered at ClinicalTrials.gov (NCT02384967). Study evaluations and statistical methods Plasma HIV-1 RNA measurements and safety assessments were performed at screening, baseline and each visit (weeks 8, 12, 16, 24, 32, 36, 40, 48, 60 and 72 or withdrawal). The mITT population included all enrolled patients who took one or more doses of trial medication, with no major violation of inclusion criteria, irrespective of protocol compliance. A minimum of 94 patients had to be enrolled to detect a difference in success rate from 80% (H0) to 90% (H1) with a type I error rate of 5% and a statistical power of 85%, through to 48 weeks in an mITT analysis. HIV RNA levels in plasma were quantified at each timepoint using the HIV-1 Cobas-Taqman v2.0 test (Roche, Meylan, France) with a detection threshold of 20 copies/mL or the Abbott Real Time HIV-1 assay with a threshold of 40 copies/mL, using for each patient the same test during follow-up. Virological failure was defined as a confirmed plasma HIV RNA level ≥50 copies/mL with the confirmatory sample taken at least 2 weeks after the first sample. Genotypic resistance tests were centralized and performed on samples with virological failure. Genotypic tests were performed using the ANRS PCR and sequencing procedure and resistance interpretation was done using the French ANRS algorithm.24 Virological blip was defined as a single plasma HIV RNA level > 50 copies/mL without confirmation. Risk factors for blips and virological failures were assessed using patients’ baseline characteristics and adherence in a multivariate analysis. Change over time in CD4 cell count from baseline to week 48 was calculated using observed data. Patient adherence was assessed at weeks 0, 12, 24, 36 and 48 using the ANRS self-report questionnaire about the number of missed doses over the last 4 days. Patients were defined as either fully adherent (no missed doses at any questionnaire) or non-fully adherent. The ITT population including all enrolled patients was used for the safety analysis. Safety was assessed using AE data, clinical laboratory tests (haematology and biochemistry) and physical examination. An independent Data and Safety Monitoring Board was implemented for continued review of the safety data. AEs and laboratory abnormalities were graded according to the ANRS Grading Table and causality was assessed by the study investigators.25 In addition, patients’ self-reported gastrointestinal symptoms (diarrhoea, nausea, pain, flatulence, constipation) were assessed at baseline and weeks 12, 24, 36 and 48 using a self-administered questionnaire based on the Gastrointestinal Symptom Rating Scale.26 Changes from baseline in these parameters were assessed by generalized linear models incorporating a subject effect. A PK sub-study of darunavir and ritonavir was performed at baseline and week 12 in 15 volunteers who had a PK blood sampling over 24 h at 0, 1, 3, 5, 8 and 24 h.27 The full results of this PK sub-study will be reported separately. Results Patient demographics and baseline characteristics From March to October 2015, 113 patients were screened at 13 sites in university hospitals in France and 100 patients were enrolled (Figure 1). Figure 1. View largeDownload slide Patient disposition up to week 48. Figure 1. View largeDownload slide Patient disposition up to week 48. Baseline patient characteristics are shown in Table 1. Most patients were male (78%); median age was 43 years, median duration of plasma HIV RNA ≤50 copies/mL was 35 months and median CD4 T cell count was 633 cells/mm3. The NRTIs used were TDF/FTC (76%) and ABC/3TC (24%). At baseline, one patient had a plasma HIV RNA > 50 copies/mL, which was not confirmed on follow-up testing. Table 1. Patient baseline characteristics Characteristic Median (IQR) or n (%) (N = 100) Age (years) 43 (37–48) Male sex 78 (78) MSM 55 (55) Body weight (kg) 72.5 (67–82.5) History of AIDS 11 (11) Duration of ART (months) 46 (31–63) CD4 cell count (cells/mm3) 633 (513–770) CD4 cell count nadir (cells/mm3) 297 (201–376) Peak plasma HIV RNA level (log10 copies/mL) 4.9 (4.4–5.4) Duration of HIV RNA plasma levels <50 copies/mL (months) 35 (22–52) Hepatitis B or C co-infection 12 (12) Tenofovir + emtricitabine 76 (76) Abacavir + lamivudine 24 (24) Characteristic Median (IQR) or n (%) (N = 100) Age (years) 43 (37–48) Male sex 78 (78) MSM 55 (55) Body weight (kg) 72.5 (67–82.5) History of AIDS 11 (11) Duration of ART (months) 46 (31–63) CD4 cell count (cells/mm3) 633 (513–770) CD4 cell count nadir (cells/mm3) 297 (201–376) Peak plasma HIV RNA level (log10 copies/mL) 4.9 (4.4–5.4) Duration of HIV RNA plasma levels <50 copies/mL (months) 35 (22–52) Hepatitis B or C co-infection 12 (12) Tenofovir + emtricitabine 76 (76) Abacavir + lamivudine 24 (24) Table 1. Patient baseline characteristics Characteristic Median (IQR) or n (%) (N = 100) Age (years) 43 (37–48) Male sex 78 (78) MSM 55 (55) Body weight (kg) 72.5 (67–82.5) History of AIDS 11 (11) Duration of ART (months) 46 (31–63) CD4 cell count (cells/mm3) 633 (513–770) CD4 cell count nadir (cells/mm3) 297 (201–376) Peak plasma HIV RNA level (log10 copies/mL) 4.9 (4.4–5.4) Duration of HIV RNA plasma levels <50 copies/mL (months) 35 (22–52) Hepatitis B or C co-infection 12 (12) Tenofovir + emtricitabine 76 (76) Abacavir + lamivudine 24 (24) Characteristic Median (IQR) or n (%) (N = 100) Age (years) 43 (37–48) Male sex 78 (78) MSM 55 (55) Body weight (kg) 72.5 (67–82.5) History of AIDS 11 (11) Duration of ART (months) 46 (31–63) CD4 cell count (cells/mm3) 633 (513–770) CD4 cell count nadir (cells/mm3) 297 (201–376) Peak plasma HIV RNA level (log10 copies/mL) 4.9 (4.4–5.4) Duration of HIV RNA plasma levels <50 copies/mL (months) 35 (22–52) Hepatitis B or C co-infection 12 (12) Tenofovir + emtricitabine 76 (76) Abacavir + lamivudine 24 (24) Five patients were excluded from the mITT analysis: three because they experienced previous virological failure (two with RAMs) and one because of pregnancy, all of whom switched back to the 800/100 mg dose of darunavir/r, and one because of consent withdrawal before starting the low-dose darunavir/r regimen. Eight out of 95 (8.4%) patients enrolled in the mITT analysis prematurely discontinued darunavir/r 400/100 mg during the first 48 weeks of follow-up: one because of pregnancy, one due to physician decision and six because of a confirmed plasma HIV RNA level >50 copies/mL. No patient discontinued the study because of AEs or loss to follow-up. Efficacy through to week 48 Through to week 48, 87 out of 95 patients maintained a plasma HIV RNA level <50 copies/mL, with a treatment success rate of 91.6% (87/95; 95% CI 84.1%–96.3%); therefore, excluding the null hypothesis of an efficacy of only 80%. There was a moderate increase in median CD4 cell count from baseline to week 48 of 40 cells/mm3 (P = 0.049). Six patients (6.3%) experienced virological failure during the first 48 weeks of the trial, with a confirmed plasma HIV RNA level >50 copies/mL. Only two patients had confirmed plasma HIV RNA levels >200 copies/mL and in these two patients there was obvious non-adherence to the study regimen, with treatment discontinuation for several weeks. Genotypic resistance testing was attempted in cases of virological failure using all plasma samples with >50 copies/mL. The reverse transcriptase and protease genes were amplifiable in only three subjects, including the two subjects that had confirmed plasma HIV RNA levels >200 copies/mL; none of them showed PI or NRTI RAMs. Eleven additional patients experienced at least a single episode of plasma HIV RNA >50 copies/mL (blip) during the first 48 weeks of follow-up. When analysing risk factors for plasma HIV RNA levels >50 copies/mL (virological failure or blips), only a plasma HIV RNA level above the assay threshold at screening or baseline was significantly associated with virological failure or blipsm, with an OR of 4.76 (95% CI 1.47–15.4) (Table 2). Table 2. Risk factors for plasma HIV RNA levels >50 copies/mL (blips and virological failure) during the first 48 weeks of follow-up Variable OR (95% CI) P value Age (years) 0.98 (0.92–1.04) 0.54 Female sex 1.19 (0.34–4.15) 0.78 Sexual orientation other than MSM 1.53 (0.54–4.40) 0.43 Body weight 0.98 (0.94–1.03) 0.47 Duration of ART (months) 0.99 (0.96–1.01) 0.25 Baseline CD4 cell count (per 100 cells/mm3) 1.03 (0.82–1.29) 0.79 Screen and/or baseline plasma HIV RNA above assay thresholda 4.76 (1.47–15.4) 0.009 Peak plasma HIV RNA level (log10 copies/mL) 2.06 (1.00–4.25) 0.05 Duration of plasma HIV RNA <50 copies/mL (months) 0.98 (0.95–1.01) 0.17 Fully therapy adherent at all visits 0.67 (0.21–2.16) 0.50 TDF/FTC versus ABC/3TC 2.42 (0.51–11.5) 0.27 Variable OR (95% CI) P value Age (years) 0.98 (0.92–1.04) 0.54 Female sex 1.19 (0.34–4.15) 0.78 Sexual orientation other than MSM 1.53 (0.54–4.40) 0.43 Body weight 0.98 (0.94–1.03) 0.47 Duration of ART (months) 0.99 (0.96–1.01) 0.25 Baseline CD4 cell count (per 100 cells/mm3) 1.03 (0.82–1.29) 0.79 Screen and/or baseline plasma HIV RNA above assay thresholda 4.76 (1.47–15.4) 0.009 Peak plasma HIV RNA level (log10 copies/mL) 2.06 (1.00–4.25) 0.05 Duration of plasma HIV RNA <50 copies/mL (months) 0.98 (0.95–1.01) 0.17 Fully therapy adherent at all visits 0.67 (0.21–2.16) 0.50 TDF/FTC versus ABC/3TC 2.42 (0.51–11.5) 0.27 a 88 patients were tested with the Roche assay (threshold of 20 copies/mL) and 12 with the Abbott assay (threshold of 40 copies/mL). Table 2. Risk factors for plasma HIV RNA levels >50 copies/mL (blips and virological failure) during the first 48 weeks of follow-up Variable OR (95% CI) P value Age (years) 0.98 (0.92–1.04) 0.54 Female sex 1.19 (0.34–4.15) 0.78 Sexual orientation other than MSM 1.53 (0.54–4.40) 0.43 Body weight 0.98 (0.94–1.03) 0.47 Duration of ART (months) 0.99 (0.96–1.01) 0.25 Baseline CD4 cell count (per 100 cells/mm3) 1.03 (0.82–1.29) 0.79 Screen and/or baseline plasma HIV RNA above assay thresholda 4.76 (1.47–15.4) 0.009 Peak plasma HIV RNA level (log10 copies/mL) 2.06 (1.00–4.25) 0.05 Duration of plasma HIV RNA <50 copies/mL (months) 0.98 (0.95–1.01) 0.17 Fully therapy adherent at all visits 0.67 (0.21–2.16) 0.50 TDF/FTC versus ABC/3TC 2.42 (0.51–11.5) 0.27 Variable OR (95% CI) P value Age (years) 0.98 (0.92–1.04) 0.54 Female sex 1.19 (0.34–4.15) 0.78 Sexual orientation other than MSM 1.53 (0.54–4.40) 0.43 Body weight 0.98 (0.94–1.03) 0.47 Duration of ART (months) 0.99 (0.96–1.01) 0.25 Baseline CD4 cell count (per 100 cells/mm3) 1.03 (0.82–1.29) 0.79 Screen and/or baseline plasma HIV RNA above assay thresholda 4.76 (1.47–15.4) 0.009 Peak plasma HIV RNA level (log10 copies/mL) 2.06 (1.00–4.25) 0.05 Duration of plasma HIV RNA <50 copies/mL (months) 0.98 (0.95–1.01) 0.17 Fully therapy adherent at all visits 0.67 (0.21–2.16) 0.50 TDF/FTC versus ABC/3TC 2.42 (0.51–11.5) 0.27 a 88 patients were tested with the Roche assay (threshold of 20 copies/mL) and 12 with the Abbott assay (threshold of 40 copies/mL). The proportion of patients with a plasma HIV RNA level below the threshold for quantification remained unchanged during follow-up, from 81% at baseline to 80.7% at week 48 (data not shown). Efficacy during extended follow-up Sixty-eight patients extended follow-up beyond week 48 by a median of 91 days (range 84–186). During extended follow-up, two additional patients presented with virological failure; only one of them had a plasma HIV RNA level above the 200 copies/mL threshold, and in this patient no RAM was detected on the resistance genotypic test. This patient was not fully adherent to the treatment regimen. Adherence Based on self-administered questionnaires, 73/95 (76.8%) patients were fully adherent to their study drugs at all visits during the first 48 weeks of follow-up. The three patients who failed during the entire study follow-up, with a plasma HIV RNA level >200 copies/mL, were all non-fully adherent to their regimen. Safety Sixty-four patients presented a total of 212 AEs, most being gastrointestinal AEs (23%) (Table 3). Serious AEs were reported in only nine patients: cerebrovascular ischaemia, endocarditis, neutropenia, dog bite, sciatalgia, prostate cancer, diarrhoea, iatrogenic Cushing syndrome, post-traumatic bone fracture and abdominal pain. None of these was considered drug-related by the investigators. No patient discontinued the study regimen because of an AE. Table 3. Summary of safety Characteristic Once-daily darunavir/ ritonavir 400/100 mg (n = 100) ≥1 AE 64 ≥1 serious AE 9 ≥1 AE leading to discontinuation 0 Death 0  Gastrointestinal AEs 23  nausea/vomiting 2  diarrhoea 9  abdominal pain 5 Laboratory abnormalities grade 2–3 14  neutrophils <1000/mm3 4a  white blood cells <2000/mm3 1  total cholesterol >7.75 mmol/L 1  triglycerides >4.5 mmol/L 2  phosphataemia <1.5 mmol/L 2  glucose >7 mmol/L 3  ALT ≥2.5 × ULN 2a  AST ≥2.5 × ULN 1  γ-glutamyl transferase ≥2.5 × ULN 1 Characteristic Once-daily darunavir/ ritonavir 400/100 mg (n = 100) ≥1 AE 64 ≥1 serious AE 9 ≥1 AE leading to discontinuation 0 Death 0  Gastrointestinal AEs 23  nausea/vomiting 2  diarrhoea 9  abdominal pain 5 Laboratory abnormalities grade 2–3 14  neutrophils <1000/mm3 4a  white blood cells <2000/mm3 1  total cholesterol >7.75 mmol/L 1  triglycerides >4.5 mmol/L 2  phosphataemia <1.5 mmol/L 2  glucose >7 mmol/L 3  ALT ≥2.5 × ULN 2a  AST ≥2.5 × ULN 1  γ-glutamyl transferase ≥2.5 × ULN 1 ULN, upper limit of normal. a One grade 3 event. Table 3. Summary of safety Characteristic Once-daily darunavir/ ritonavir 400/100 mg (n = 100) ≥1 AE 64 ≥1 serious AE 9 ≥1 AE leading to discontinuation 0 Death 0  Gastrointestinal AEs 23  nausea/vomiting 2  diarrhoea 9  abdominal pain 5 Laboratory abnormalities grade 2–3 14  neutrophils <1000/mm3 4a  white blood cells <2000/mm3 1  total cholesterol >7.75 mmol/L 1  triglycerides >4.5 mmol/L 2  phosphataemia <1.5 mmol/L 2  glucose >7 mmol/L 3  ALT ≥2.5 × ULN 2a  AST ≥2.5 × ULN 1  γ-glutamyl transferase ≥2.5 × ULN 1 Characteristic Once-daily darunavir/ ritonavir 400/100 mg (n = 100) ≥1 AE 64 ≥1 serious AE 9 ≥1 AE leading to discontinuation 0 Death 0  Gastrointestinal AEs 23  nausea/vomiting 2  diarrhoea 9  abdominal pain 5 Laboratory abnormalities grade 2–3 14  neutrophils <1000/mm3 4a  white blood cells <2000/mm3 1  total cholesterol >7.75 mmol/L 1  triglycerides >4.5 mmol/L 2  phosphataemia <1.5 mmol/L 2  glucose >7 mmol/L 3  ALT ≥2.5 × ULN 2a  AST ≥2.5 × ULN 1  γ-glutamyl transferase ≥2.5 × ULN 1 ULN, upper limit of normal. a One grade 3 event. Analysis of self-reported gastrointestinal tolerability questionnaires showed a small but significant improvement from baseline in diarrhoea with the reduction in darunavir dose (Figure 2, P = 0.01). Figure 2. View largeDownload slide Changes from baseline in the self-reported gastrointestinal symptom score (higher score was associated with worse symptoms). Only changes from baseline in diarrhoea score significantly improved (P = 0.01). Figure 2. View largeDownload slide Changes from baseline in the self-reported gastrointestinal symptom score (higher score was associated with worse symptoms). Only changes from baseline in diarrhoea score significantly improved (P = 0.01). No patient died during the study. The two pregnant women who switched back to darunavir/r 800/100 mg delivered healthy non-HIV-infected babies. The overall incidence of laboratory abnormalities was low, with most being grade 1 or 2 in severity, and only 14 patients experienced grade 2 or worse laboratory abnormalities, with two grade 3 events (one episode of neutropenia and one episode of ALT elevation) (Table 3). The most frequently reported treatment-emergent grade 2–3 laboratory abnormalities were neutropenia, hyperglycaemia and lipid abnormalities. Changes from baseline to week 48 in fasting lipid-related laboratory parameters (total cholesterol, HDL and LDL cholesterol and triglycerides), glycaemia and plasma CLCR were minimal and non-significant (data not shown). Discussion The results from this single-arm, Phase II, open-label trial in well-suppressed treatment-experienced patients with no darunavir or NRTI RAMs and no previous virological failure demonstrated that over 48 weeks of treatment a switch from once-daily darunavir/r 800/100 mg to darunavir/r 400/100 mg with the same two NRTIs was associated with a high rate of virological suppression of 91.6%. Patients enrolled in the ANRS 165 Darulight study had a long history of treatment with a median of 46 months of antiretroviral therapy, were virologically suppressed for a median of 35 months and had high CD4 cell counts at baseline. These results are consistent with a subset analysis of the POWER 1 and 2 studies in patients with HIV strains susceptible to darunavir, which showed similar virological response rates with once-daily darunavir/r 400/100 and 800/100 mg (78% and 74%, respectively, at week 24).28–29 In addition, clinical trials of darunavir/r in PI-naive or -experienced patients have shown no correlation between PK exposure to darunavir and plasma HIV RNA suppression, when HIV-1 was susceptible to darunavir, suggesting that the optimal dose of darunavir in patients with a susceptible strain is as yet unknown.30,31 It is also reassuring that preliminary PK data reported from the ANRS 165 Darulight study showed a similar AUC of darunavir at the dose of 800/100 or 400/100 mg, with an increase in ritonavir AUC with the low darunavir dose probably because of lower induction on ritonavir.27 In addition, two small pilot studies have also reported high virological suppression rates of 88.5%–90% in patients using once-daily darunavir/r at the 600/100 mg dose.15–16 This strategy of low-dose boosted PIs has also been successful with another PI (atazanavir) in the setting of a large randomized trial, and it would be interesting to confirm the efficacy of the low-dose darunavir/r 400/100 mg in a randomized trial.14 Such a trial is currently ongoing in South Africa (NCT02671383) evaluating, in well-suppressed patients on a PI-based second-line therapy with lopinavir/ritonavir, the non-inferiority of a switch to darunavir/r (400/100 mg) + two NRTIs. Should this trial confirm our findings, this strategy could lead to significant savings for second-line therapy in low- and middle-income countries. In addition, some tolerability benefits could be also associated with this reduced dose, as shown in our study, with a slight reduction in self-reported diarrhoea. Our study has, however, a number of limitations. It was an open-label, non-randomized, one-arm study, with a limited follow-up of only 48 weeks and a limited number of patients enrolled. As such, this trial could not be considered as providing a definite answer regarding the benefit of this dose reduction strategy, which will require evidence based on ongoing Phase III randomized studies. In addition, although the overall success rate was >80%, 6/95 patients (6.3%) experienced virological failure over the first 48 weeks of follow-up and two additional patients did so during extended follow-up, all of whom were fully suppressed at baseline. This rate of virological failure is, however, consistent with previous darunavir/r switch trials in well-suppressed patients. In the MONET trial, 7/129 (5.4%) patients randomized in the darunavir/r + two NRTIs arm experienced a confirmed plasma HIV RNA level >50 copies/mL during follow-up, but the treatment was not changed and at the end of 48 weeks only one patient had a plasma HIV RNA level >50 copies/mL.32 In the ANRS MONOI trial, only 81% of patients randomized to the triple arm of darunavir/r + two NRTIs had sustained plasma HIV RNA levels <50 copies/mL at week 48.33 In the SPIRIT study (Switching boosted Protease Inhibitor to Rilpivirine in combination with Tenofovir/emtricitabine), the rate of virological failure >50 copies/mL in the boosted PI arm was 5% at week 24.34 Because these low levels of plasma HIV RNA replication in patients with regimens based on boosted PIs rarely select for drug RAMs due to the high genetic barrier for the development of resistance to boosted PIs, a number of trials with boosted PIs used a higher plasma HIV RNA threshold to define virological failure, ranging from 200 to 400 copies/mL.14,33 Indeed, in our study over the 72 weeks of follow-up only three of eight patients with plasma HIV RNA >50 copies/mL had a plasma viral load >200 copies/mL and none had emerging NRTI or PI RAMs. Interestingly, the only risk factor for a plasma HIV RNA >50 copies/mL during follow-up was a viral load above the assay threshold at baseline or screening, suggesting that these patients did not have full suppression of viral replication. Nevertheless, this rate of virological failure at 48 weeks in our study seems higher than that reported in more recent switch trials with single-tablet cobicistat-boosted darunavir/tenofovir/emtricitabine in the EMERALD study (2.1% virological failure), or in the STRATEGY-PI trial, where patients maintaining a ritonavir-boosted PI regimen had a 1.4% rate of virological failure, and the results of well-powered randomized trials with low-dose darunavir/r are awaited.4,35 In addition, our results could not be extrapolated to the combination of darunavir with cobicistat because a PK study has reported a 30% reduction in darunavir Cmin levels when boosted with cobicistat as compared with ritonavir, which represents another limitation of our findings because darunavir is now coformulated with cobicistat.36 In conclusion, our pilot study suggests that among well-suppressed patients under a once-daily darunavir/r-based regimen at the standard dose of 800/100 mg with two NRTIs, with no previous virological failure and no darunavir or NRTI RAMS, a switch to a reduced dose of darunavir/r (400/100 mg) is associated with a high rate of virological suppression through to 48 weeks and has a favourable safety and tolerability profile. These results need confirmation in a large randomized trial before this reduced dose of darunavir/r can be recommended in clinical practice. Acknowledgements We thank the patients for their participation and support during the study. We thank Samir Messaoudene for help in conducting the study. We also thank Soizic Le Mestre and Severine Gibowski from ANRS for their help in implementing the study. ANRS 165 Darulight data were previously presented at the 9th International AIDS Society Conference on HIV Science, 23–26 July 2017, Paris, France (abstract MOPEB0313). Members of the ANRS 165 Darulight Study Team The ANRS 165 Darulight study team included the following investigators and co-investigators not listed among the authors: Hopital Saint-Louis, Paris: Dr D. Ponscarme, Dr C. Lascoux; Hopital Saint-Antoine, Paris: Prof. P. M. Girard; Hopital Lariboisière, Paris: Dr A. Rami; Hopital Bichat, Paris: Prof. Y. Yazdanpanah; Hopital Pitié Salpétrière, Internal Medicine: Dr A. Simon; Hopital Pitié Salpêtrière, Infectious Diseases: Dr R. Tubiana; Hopital Pasteur-Necker: Dr C. Duvivier; Hopital Jean Verdier, Bondy: Dr V. Jeantils; Hopital de Nimes: Dr D. Loreillard; Hopital Ste Marguerite, Marseille: Dr I. Poizot-Martin; CHU de Tours: Prof. L. Bernard, Dr G. Gras; CHU de Nantes: Dr C. Allavena, Dr C. Bernaud, Dr S. Bouchez, Dr N. Hall, Dr V. Reliquet, Prof. F. Raffi. Members of the DSMB included: Dr P. De Truchis, I. Charreau, Dr L. Bocquet, Prof. V. Lemoing and G. Point. Members of the scientific committee included: Prof. J. M. Molina, Prof. S. Chevret, E. M. El Abbassi, Dr S. Gallien, Prof. P. Tattevin, Dr G. Gras, Dr M. L. Chaix, Dr G. Peytavin, J. Saillard, S. Couffin-Cadiergues, I. Madelaine, A. Diallo and S. Gibowski. Funding The ANRS 165 Darulight study was funded by ANRS (French National Agency for Research on AIDS and viral hepatitis). Transparency declarations J-M. M. has participated in advisory boards for Gilead, Merck, Janssen, ViiV, Bristol Myers Squibb and Teva, and his institution has received grants from Merck and Gilead. S. G. has received travel grants or honoraria from Gilead Sciences, Janssen and Merck, and his institution has received grants from Pfizer. F. R. has received research funding or honoraria from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, ViiV and Healthcare. P. D. has received travel grants from Bristol Myers Squibb, Janssen and Merck, and his institution has received grants from ViiV Healthcare.  The remaining authors have none to declare. Author contributions All authors contributed to critical revision of the paper for important intellectual content and provided final approval of the version to be published. Substantial contributions to acquisition of data were made by the following authors in their role as principal investigators at their study site: J.-M. M. (Paris, Saint-Louis); S. G. (Henri-Mondor, Creteil), C. K. (Pitié-Salpétrière, Paris), F. R. (Université de Nantes), N. V. (Saint-Antoine, Paris), P. D. (CHU de Toulouse). Substantial contributions to study conception and design, and analysis and interpretation of the data were made M.-L. C., G. P., J. S., I. M., K. D., E. M. El A. and S. C. References 1 GBD 2015 HIV Collaborators . Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 2015 . Lancet HIV 2016 ; 3 : e361 – 87 . CrossRef Search ADS PubMed 2 Molina JM. Efficacy and safety of once-daily regimens in the treatment of HIV infection . Drugs 2008 ; 68 : 567 – 78 . Google Scholar CrossRef Search ADS PubMed 3 Parienti JJ , Bangsberg DR , Verdon R et al. Better adherence with once-daily antiretroviral regimens: a meta-analysis . Clin Infect Dis 2009 ; 48 : 484 – 8 . Google Scholar CrossRef Search ADS PubMed 4 Orkin C , Molina JM , Negredo E et al. ; EMERALD study group . 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Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naïve HIV-1-infected patients at week 48 . AIDS 2008 ; 22 : 1389 – 97 . Google Scholar CrossRef Search ADS PubMed 18 Mills AM , Nelson M , Jayaweera D et al. Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis . AIDS 2009 ; 23 : 1679 – 88 . Google Scholar CrossRef Search ADS PubMed 19 Cahn P , Fourie J , Grinsztejn B et al. Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients . AIDS 2011 ; 25 : 929 – 39 . Google Scholar CrossRef Search ADS PubMed 20 De Meyer S , Spinosa-Guzman S , Vangeneugden T et al. Efficacy of once-daily darunavir/ritonavir 800/100 mg in HIV-infected, treatment-experienced patients with no baseline resistance-associated mutations to darunavir . J Acquir Immune Defic Syndr 2008 ; 49 : 179 – 82 . 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January 2015. http://www.hivfrenchresistance.org/ANRS-procedures.pdf. 25 ANRS. Scale to Grade the Severity of Adverse Events in Adults. Version 1.0, 4 November 2008. http://www.anrs.fr/Rubriques-transversales/Outils-pour-la-recherche. 26 Sáez de la Fuente J , Granja V , Escobar I et al. Study of the gastrointestinal tolerance of a new tablet formulation of the lopinavir/ritonavir antiretroviral in HIV-infected patients . J Acquir Immune Defic Syndr 2009 ; 50 : 294 – 8 . Google Scholar CrossRef Search ADS PubMed 27 Le MP , Molina JM , Madelain V et al. Pharmacokinetic modeling of darunavir/ritonavir dose reduction (800/100 mg to 400/100 mg once daily) containing regimen in virologically suppressed HIV-infected patients as maintenance therapy: ANRS 165 Darulight sub-study. In: Abstracts of the Ninth IAS Conference on HIV Science, Paris, France, 2017. Abstract MOPEB0329. 28 Haubrich R , Berger D , Chiliade P et al. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients . AIDS 2007 ; 21 : F11 – 8 . Google Scholar CrossRef Search ADS PubMed 29 Katlama C , Esposito R , Gatell JM et al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1 . AIDS 2007 ; 21 : 395 – 402 . Google Scholar CrossRef Search ADS PubMed 30 Sekar V , Vanden Abeele C , Van Baelen B et al. Pharmacokinetic-pharmacodynamic analyses of once-daily darunavir-ritonavir in the ARTEMIS study. In: Abstracts of the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, 2008. Abstract 769. 31 Sekar V , De La Rosa G , de Casteele T et al. Pharmacokinetic and pharmacodynamic analyses of once- and twice-daily darunavir/ritonavir in the ODIN trial . J Int AIDS Soc 2010 ; 13 Suppl 4: 98 (abstract P185). 32 Arribas JR , Horban A , Gerstoft J et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/mL . AIDS 2010 ; 24 : 223 – 30 . Google Scholar CrossRef Search ADS PubMed 33 Katlama C , Valantin MA , Algarte-Genin M et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136 . AIDS 2010 ; 24 : 2365 – 74 . Google Scholar PubMed 34 Palella FJ Jr , Fisher M , Tebas P et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants . AIDS 2014 ; 28 : 335 – 44 . Google Scholar CrossRef Search ADS PubMed 35 Arribas JR , Pialoux G , Gathe J et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial . Lancet Infect Dis 2014 ; 14 : 581 – 9 . Google Scholar CrossRef Search ADS PubMed 36 Kakuda TN , Opsomer M , Timmers M et al. Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers . J Clin Pharmacol 2014 ; 54 : 949 – 57 . 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

Low-dose ritonavir-boosted darunavir in virologically suppressed HIV-1-infected adults: an open-label trial (ANRS 165 Darulight)

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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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0305-7453
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1460-2091
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10.1093/jac/dky181
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Abstract

Abstract Objectives To assess whether low-dose ritonavir-boosted darunavir (darunavir/r) in combination with two NRTIs could maintain virological suppression in patients on a standard regimen of darunavir/r + two NRTIs. Design A multicentre, Phase II, non-comparative, single-arm, open-label study. Setting Tertiary care hospitals in France. Subjects One hundred HIV-1-infected adults with no darunavir or NRTI resistance-associated mutations (RAMs) and a plasma HIV RNA level ≤50 copies/mL for ≥12 months on once-daily darunavir/r (800/100 mg) + two NRTIs for ≥6 months were switched to darunavir/r 400/100 mg with the same NRTIs. Primary outcome measure Proportion of patients with treatment success: plasma HIV RNA level ≤50  copies/mL up to 48 weeks without any change in the study regimen, in a modified ITT (mITT) analysis. Results At baseline, most patients were male (78%), with a median age of 43 years, median duration of HIV RNA ≤50 copies/mL of 35 months and median CD4 T cell count of 633 cells/mm3. Seventy-six percent received tenofovir/emtricitabine and 24% abacavir/lamivudine. Five patients were excluded from the mITT analysis. The rate of treatment success through to week 48 was 91.6% (87/95; 95% CI 84.1%–96.3%). No RAM was detected in three amplifiable genotypes. A total of 212 adverse events (AEs) occurred in 64 patients (64%); 9 AEs were serious, none leading to treatment discontinuation. Conclusions In HIV-infected patients well suppressed with darunavir/r (800/100 mg) and two NRTIs, a reduction of the darunavir dose to 400 mg/day maintained virological efficacy and was safe over 48 weeks. Introduction Continuous improvements in the treatment of HIV infection have led to high rates of sustained virological suppression and good tolerability, thereby reducing morbidity and mortality.1 However, because treatment is life-long, simplified regimens are needed to improve convenience and adherence, and to reduce drug-related adverse events (AEs) and cost.2–3 Among current strategies being assessed to improve antiretroviral therapies, such as co-formulation of multiple agents in a single pill and dual therapy or long-acting injectable agents, dose reduction of antiretroviral agents has been less frequently investigated.4–6 WHO has, however, recently updated its guidelines to recommend low-dose efavirenz (400 mg daily instead of 600 mg) as an alternative first-line regimen in low- and middle-income countries, following the results of a large randomized trial.7–9 PIs, despite a unique high genetic barrier to the development of resistance when boosted with low-dose ritonavir (r), have been moved to alternative or second-line regimens because of their imperfect tolerability profile and high cost.7–10 Pioneering studies that demonstrated that lower doses of ritonavir-boosted indinavir induced and maintained adequate virological suppression with improved safety and adequate PK established an interest in examining lowered doses of boosted PIs.11–13 Few studies thereafter have assessed the safety and efficacy of low-dose second-generation PIs in combination with other antiretroviral agents, which might improve tolerability and reduce costs.14–16 Once-daily ritonavir-boosted darunavir (darunavir/r) at the dose of 800/100 mg has demonstrated durable efficacy in both treatment-naive and treatment-experienced patients with no darunavir resistance-associated mutations (RAMs), and a better tolerability profile than ritonavir-boosted atazanavir.17–21 We wished to investigate a reduced dose of darunavir (400 mg) in combination with ritonavir in well-suppressed patients on the standard dose of once-daily darunavir/r + two NRTIs. Patients and methods Patient population Patients enrolled in the ANRS 165 Darulight study were treatment-experienced, HIV-1-infected adults (≥18 years), with a plasma HIV-1 RNA ≤50 copies/mL for at least 12 months, no previous virological failure, defined as a plasma HIV RNA >200 copies/mL, CD4 cell count >300 cells/mm3 and none of the 11 darunavir (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V) or NRTI RAMs detected by a resistance genotype test before treatment initiation.22 Patients needed to be receiving a stable darunavir-containing regimen for ≥6 months at screening with once-daily darunavir/r (800/100 mg) + two NRTIs [tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC)]. Patients with chronic hepatitis B and/or C infection were allowed to enrol if their condition was clinically stable and they were not expected to require treatment during the study period. Other exclusion criteria included HIV-2 infection, the presence of any active AIDS-defining illness, use of disallowed concomitant therapy, pregnancy/breastfeeding, and laboratory abnormalities (ALT or AST levels >2-fold the upper limit of normal, haemoglobin level <11 g/dL, platelet count <150 000/mm3), or estimated CLCR using the Cockroft–Gault equation <60 mL/min if tenofovir disoproxil fumarate was used. Study design ANRS 165 Darulight was a multicentre Phase II, non-comparative, single-arm, open-label study assessing the efficacy, safety and tolerability of switching from once-daily darunavir/r 800/100 mg + two NRTIs to once-daily darunavir/r 400/100 mg with the same two NRTIs, over 48 weeks in well-suppressed treatment-experienced patients with no darunavir or NRTI RAMs. Study treatments were delivered every 2 months at each hospital pharmacy site and patients received, in addition to their NRTI backbone (TDF/FTC or ABC/3TC), a bottle of 60 pills containing 400 mg of darunavir and 60 pills containing 100 mg of ritonavir. The study drugs had to be taken once daily with food to increase darunavir bioavailability.23 The trial consisted of a screening period (up to 4 weeks), a 48 week treatment period, and an extended follow-up of 24 weeks up to week 72 until the last participant completed the 48 week visit. The primary objective was to establish the proportion of patients with treatment success through to 48 weeks, defined as plasma HIV RNA levels ≤50 copies/mL without any change in the darunavir/r dose, in a modified ITT (mITT) analysis. The primary analysis was performed when all actively enrolled patients had completed 48 weeks. Written informed consent was obtained from all study participants. The study protocol was reviewed and approved by the Paris Saint-Louis ethics committee (Comité de Protection des Personnes) and health authority (EudraCT number 2014-001505-40), was conducted in accordance with good clinical practice and the Declaration of Helsinki, and was registered at ClinicalTrials.gov (NCT02384967). Study evaluations and statistical methods Plasma HIV-1 RNA measurements and safety assessments were performed at screening, baseline and each visit (weeks 8, 12, 16, 24, 32, 36, 40, 48, 60 and 72 or withdrawal). The mITT population included all enrolled patients who took one or more doses of trial medication, with no major violation of inclusion criteria, irrespective of protocol compliance. A minimum of 94 patients had to be enrolled to detect a difference in success rate from 80% (H0) to 90% (H1) with a type I error rate of 5% and a statistical power of 85%, through to 48 weeks in an mITT analysis. HIV RNA levels in plasma were quantified at each timepoint using the HIV-1 Cobas-Taqman v2.0 test (Roche, Meylan, France) with a detection threshold of 20 copies/mL or the Abbott Real Time HIV-1 assay with a threshold of 40 copies/mL, using for each patient the same test during follow-up. Virological failure was defined as a confirmed plasma HIV RNA level ≥50 copies/mL with the confirmatory sample taken at least 2 weeks after the first sample. Genotypic resistance tests were centralized and performed on samples with virological failure. Genotypic tests were performed using the ANRS PCR and sequencing procedure and resistance interpretation was done using the French ANRS algorithm.24 Virological blip was defined as a single plasma HIV RNA level > 50 copies/mL without confirmation. Risk factors for blips and virological failures were assessed using patients’ baseline characteristics and adherence in a multivariate analysis. Change over time in CD4 cell count from baseline to week 48 was calculated using observed data. Patient adherence was assessed at weeks 0, 12, 24, 36 and 48 using the ANRS self-report questionnaire about the number of missed doses over the last 4 days. Patients were defined as either fully adherent (no missed doses at any questionnaire) or non-fully adherent. The ITT population including all enrolled patients was used for the safety analysis. Safety was assessed using AE data, clinical laboratory tests (haematology and biochemistry) and physical examination. An independent Data and Safety Monitoring Board was implemented for continued review of the safety data. AEs and laboratory abnormalities were graded according to the ANRS Grading Table and causality was assessed by the study investigators.25 In addition, patients’ self-reported gastrointestinal symptoms (diarrhoea, nausea, pain, flatulence, constipation) were assessed at baseline and weeks 12, 24, 36 and 48 using a self-administered questionnaire based on the Gastrointestinal Symptom Rating Scale.26 Changes from baseline in these parameters were assessed by generalized linear models incorporating a subject effect. A PK sub-study of darunavir and ritonavir was performed at baseline and week 12 in 15 volunteers who had a PK blood sampling over 24 h at 0, 1, 3, 5, 8 and 24 h.27 The full results of this PK sub-study will be reported separately. Results Patient demographics and baseline characteristics From March to October 2015, 113 patients were screened at 13 sites in university hospitals in France and 100 patients were enrolled (Figure 1). Figure 1. View largeDownload slide Patient disposition up to week 48. Figure 1. View largeDownload slide Patient disposition up to week 48. Baseline patient characteristics are shown in Table 1. Most patients were male (78%); median age was 43 years, median duration of plasma HIV RNA ≤50 copies/mL was 35 months and median CD4 T cell count was 633 cells/mm3. The NRTIs used were TDF/FTC (76%) and ABC/3TC (24%). At baseline, one patient had a plasma HIV RNA > 50 copies/mL, which was not confirmed on follow-up testing. Table 1. Patient baseline characteristics Characteristic Median (IQR) or n (%) (N = 100) Age (years) 43 (37–48) Male sex 78 (78) MSM 55 (55) Body weight (kg) 72.5 (67–82.5) History of AIDS 11 (11) Duration of ART (months) 46 (31–63) CD4 cell count (cells/mm3) 633 (513–770) CD4 cell count nadir (cells/mm3) 297 (201–376) Peak plasma HIV RNA level (log10 copies/mL) 4.9 (4.4–5.4) Duration of HIV RNA plasma levels <50 copies/mL (months) 35 (22–52) Hepatitis B or C co-infection 12 (12) Tenofovir + emtricitabine 76 (76) Abacavir + lamivudine 24 (24) Characteristic Median (IQR) or n (%) (N = 100) Age (years) 43 (37–48) Male sex 78 (78) MSM 55 (55) Body weight (kg) 72.5 (67–82.5) History of AIDS 11 (11) Duration of ART (months) 46 (31–63) CD4 cell count (cells/mm3) 633 (513–770) CD4 cell count nadir (cells/mm3) 297 (201–376) Peak plasma HIV RNA level (log10 copies/mL) 4.9 (4.4–5.4) Duration of HIV RNA plasma levels <50 copies/mL (months) 35 (22–52) Hepatitis B or C co-infection 12 (12) Tenofovir + emtricitabine 76 (76) Abacavir + lamivudine 24 (24) Table 1. Patient baseline characteristics Characteristic Median (IQR) or n (%) (N = 100) Age (years) 43 (37–48) Male sex 78 (78) MSM 55 (55) Body weight (kg) 72.5 (67–82.5) History of AIDS 11 (11) Duration of ART (months) 46 (31–63) CD4 cell count (cells/mm3) 633 (513–770) CD4 cell count nadir (cells/mm3) 297 (201–376) Peak plasma HIV RNA level (log10 copies/mL) 4.9 (4.4–5.4) Duration of HIV RNA plasma levels <50 copies/mL (months) 35 (22–52) Hepatitis B or C co-infection 12 (12) Tenofovir + emtricitabine 76 (76) Abacavir + lamivudine 24 (24) Characteristic Median (IQR) or n (%) (N = 100) Age (years) 43 (37–48) Male sex 78 (78) MSM 55 (55) Body weight (kg) 72.5 (67–82.5) History of AIDS 11 (11) Duration of ART (months) 46 (31–63) CD4 cell count (cells/mm3) 633 (513–770) CD4 cell count nadir (cells/mm3) 297 (201–376) Peak plasma HIV RNA level (log10 copies/mL) 4.9 (4.4–5.4) Duration of HIV RNA plasma levels <50 copies/mL (months) 35 (22–52) Hepatitis B or C co-infection 12 (12) Tenofovir + emtricitabine 76 (76) Abacavir + lamivudine 24 (24) Five patients were excluded from the mITT analysis: three because they experienced previous virological failure (two with RAMs) and one because of pregnancy, all of whom switched back to the 800/100 mg dose of darunavir/r, and one because of consent withdrawal before starting the low-dose darunavir/r regimen. Eight out of 95 (8.4%) patients enrolled in the mITT analysis prematurely discontinued darunavir/r 400/100 mg during the first 48 weeks of follow-up: one because of pregnancy, one due to physician decision and six because of a confirmed plasma HIV RNA level >50 copies/mL. No patient discontinued the study because of AEs or loss to follow-up. Efficacy through to week 48 Through to week 48, 87 out of 95 patients maintained a plasma HIV RNA level <50 copies/mL, with a treatment success rate of 91.6% (87/95; 95% CI 84.1%–96.3%); therefore, excluding the null hypothesis of an efficacy of only 80%. There was a moderate increase in median CD4 cell count from baseline to week 48 of 40 cells/mm3 (P = 0.049). Six patients (6.3%) experienced virological failure during the first 48 weeks of the trial, with a confirmed plasma HIV RNA level >50 copies/mL. Only two patients had confirmed plasma HIV RNA levels >200 copies/mL and in these two patients there was obvious non-adherence to the study regimen, with treatment discontinuation for several weeks. Genotypic resistance testing was attempted in cases of virological failure using all plasma samples with >50 copies/mL. The reverse transcriptase and protease genes were amplifiable in only three subjects, including the two subjects that had confirmed plasma HIV RNA levels >200 copies/mL; none of them showed PI or NRTI RAMs. Eleven additional patients experienced at least a single episode of plasma HIV RNA >50 copies/mL (blip) during the first 48 weeks of follow-up. When analysing risk factors for plasma HIV RNA levels >50 copies/mL (virological failure or blips), only a plasma HIV RNA level above the assay threshold at screening or baseline was significantly associated with virological failure or blipsm, with an OR of 4.76 (95% CI 1.47–15.4) (Table 2). Table 2. Risk factors for plasma HIV RNA levels >50 copies/mL (blips and virological failure) during the first 48 weeks of follow-up Variable OR (95% CI) P value Age (years) 0.98 (0.92–1.04) 0.54 Female sex 1.19 (0.34–4.15) 0.78 Sexual orientation other than MSM 1.53 (0.54–4.40) 0.43 Body weight 0.98 (0.94–1.03) 0.47 Duration of ART (months) 0.99 (0.96–1.01) 0.25 Baseline CD4 cell count (per 100 cells/mm3) 1.03 (0.82–1.29) 0.79 Screen and/or baseline plasma HIV RNA above assay thresholda 4.76 (1.47–15.4) 0.009 Peak plasma HIV RNA level (log10 copies/mL) 2.06 (1.00–4.25) 0.05 Duration of plasma HIV RNA <50 copies/mL (months) 0.98 (0.95–1.01) 0.17 Fully therapy adherent at all visits 0.67 (0.21–2.16) 0.50 TDF/FTC versus ABC/3TC 2.42 (0.51–11.5) 0.27 Variable OR (95% CI) P value Age (years) 0.98 (0.92–1.04) 0.54 Female sex 1.19 (0.34–4.15) 0.78 Sexual orientation other than MSM 1.53 (0.54–4.40) 0.43 Body weight 0.98 (0.94–1.03) 0.47 Duration of ART (months) 0.99 (0.96–1.01) 0.25 Baseline CD4 cell count (per 100 cells/mm3) 1.03 (0.82–1.29) 0.79 Screen and/or baseline plasma HIV RNA above assay thresholda 4.76 (1.47–15.4) 0.009 Peak plasma HIV RNA level (log10 copies/mL) 2.06 (1.00–4.25) 0.05 Duration of plasma HIV RNA <50 copies/mL (months) 0.98 (0.95–1.01) 0.17 Fully therapy adherent at all visits 0.67 (0.21–2.16) 0.50 TDF/FTC versus ABC/3TC 2.42 (0.51–11.5) 0.27 a 88 patients were tested with the Roche assay (threshold of 20 copies/mL) and 12 with the Abbott assay (threshold of 40 copies/mL). Table 2. Risk factors for plasma HIV RNA levels >50 copies/mL (blips and virological failure) during the first 48 weeks of follow-up Variable OR (95% CI) P value Age (years) 0.98 (0.92–1.04) 0.54 Female sex 1.19 (0.34–4.15) 0.78 Sexual orientation other than MSM 1.53 (0.54–4.40) 0.43 Body weight 0.98 (0.94–1.03) 0.47 Duration of ART (months) 0.99 (0.96–1.01) 0.25 Baseline CD4 cell count (per 100 cells/mm3) 1.03 (0.82–1.29) 0.79 Screen and/or baseline plasma HIV RNA above assay thresholda 4.76 (1.47–15.4) 0.009 Peak plasma HIV RNA level (log10 copies/mL) 2.06 (1.00–4.25) 0.05 Duration of plasma HIV RNA <50 copies/mL (months) 0.98 (0.95–1.01) 0.17 Fully therapy adherent at all visits 0.67 (0.21–2.16) 0.50 TDF/FTC versus ABC/3TC 2.42 (0.51–11.5) 0.27 Variable OR (95% CI) P value Age (years) 0.98 (0.92–1.04) 0.54 Female sex 1.19 (0.34–4.15) 0.78 Sexual orientation other than MSM 1.53 (0.54–4.40) 0.43 Body weight 0.98 (0.94–1.03) 0.47 Duration of ART (months) 0.99 (0.96–1.01) 0.25 Baseline CD4 cell count (per 100 cells/mm3) 1.03 (0.82–1.29) 0.79 Screen and/or baseline plasma HIV RNA above assay thresholda 4.76 (1.47–15.4) 0.009 Peak plasma HIV RNA level (log10 copies/mL) 2.06 (1.00–4.25) 0.05 Duration of plasma HIV RNA <50 copies/mL (months) 0.98 (0.95–1.01) 0.17 Fully therapy adherent at all visits 0.67 (0.21–2.16) 0.50 TDF/FTC versus ABC/3TC 2.42 (0.51–11.5) 0.27 a 88 patients were tested with the Roche assay (threshold of 20 copies/mL) and 12 with the Abbott assay (threshold of 40 copies/mL). The proportion of patients with a plasma HIV RNA level below the threshold for quantification remained unchanged during follow-up, from 81% at baseline to 80.7% at week 48 (data not shown). Efficacy during extended follow-up Sixty-eight patients extended follow-up beyond week 48 by a median of 91 days (range 84–186). During extended follow-up, two additional patients presented with virological failure; only one of them had a plasma HIV RNA level above the 200 copies/mL threshold, and in this patient no RAM was detected on the resistance genotypic test. This patient was not fully adherent to the treatment regimen. Adherence Based on self-administered questionnaires, 73/95 (76.8%) patients were fully adherent to their study drugs at all visits during the first 48 weeks of follow-up. The three patients who failed during the entire study follow-up, with a plasma HIV RNA level >200 copies/mL, were all non-fully adherent to their regimen. Safety Sixty-four patients presented a total of 212 AEs, most being gastrointestinal AEs (23%) (Table 3). Serious AEs were reported in only nine patients: cerebrovascular ischaemia, endocarditis, neutropenia, dog bite, sciatalgia, prostate cancer, diarrhoea, iatrogenic Cushing syndrome, post-traumatic bone fracture and abdominal pain. None of these was considered drug-related by the investigators. No patient discontinued the study regimen because of an AE. Table 3. Summary of safety Characteristic Once-daily darunavir/ ritonavir 400/100 mg (n = 100) ≥1 AE 64 ≥1 serious AE 9 ≥1 AE leading to discontinuation 0 Death 0  Gastrointestinal AEs 23  nausea/vomiting 2  diarrhoea 9  abdominal pain 5 Laboratory abnormalities grade 2–3 14  neutrophils <1000/mm3 4a  white blood cells <2000/mm3 1  total cholesterol >7.75 mmol/L 1  triglycerides >4.5 mmol/L 2  phosphataemia <1.5 mmol/L 2  glucose >7 mmol/L 3  ALT ≥2.5 × ULN 2a  AST ≥2.5 × ULN 1  γ-glutamyl transferase ≥2.5 × ULN 1 Characteristic Once-daily darunavir/ ritonavir 400/100 mg (n = 100) ≥1 AE 64 ≥1 serious AE 9 ≥1 AE leading to discontinuation 0 Death 0  Gastrointestinal AEs 23  nausea/vomiting 2  diarrhoea 9  abdominal pain 5 Laboratory abnormalities grade 2–3 14  neutrophils <1000/mm3 4a  white blood cells <2000/mm3 1  total cholesterol >7.75 mmol/L 1  triglycerides >4.5 mmol/L 2  phosphataemia <1.5 mmol/L 2  glucose >7 mmol/L 3  ALT ≥2.5 × ULN 2a  AST ≥2.5 × ULN 1  γ-glutamyl transferase ≥2.5 × ULN 1 ULN, upper limit of normal. a One grade 3 event. Table 3. Summary of safety Characteristic Once-daily darunavir/ ritonavir 400/100 mg (n = 100) ≥1 AE 64 ≥1 serious AE 9 ≥1 AE leading to discontinuation 0 Death 0  Gastrointestinal AEs 23  nausea/vomiting 2  diarrhoea 9  abdominal pain 5 Laboratory abnormalities grade 2–3 14  neutrophils <1000/mm3 4a  white blood cells <2000/mm3 1  total cholesterol >7.75 mmol/L 1  triglycerides >4.5 mmol/L 2  phosphataemia <1.5 mmol/L 2  glucose >7 mmol/L 3  ALT ≥2.5 × ULN 2a  AST ≥2.5 × ULN 1  γ-glutamyl transferase ≥2.5 × ULN 1 Characteristic Once-daily darunavir/ ritonavir 400/100 mg (n = 100) ≥1 AE 64 ≥1 serious AE 9 ≥1 AE leading to discontinuation 0 Death 0  Gastrointestinal AEs 23  nausea/vomiting 2  diarrhoea 9  abdominal pain 5 Laboratory abnormalities grade 2–3 14  neutrophils <1000/mm3 4a  white blood cells <2000/mm3 1  total cholesterol >7.75 mmol/L 1  triglycerides >4.5 mmol/L 2  phosphataemia <1.5 mmol/L 2  glucose >7 mmol/L 3  ALT ≥2.5 × ULN 2a  AST ≥2.5 × ULN 1  γ-glutamyl transferase ≥2.5 × ULN 1 ULN, upper limit of normal. a One grade 3 event. Analysis of self-reported gastrointestinal tolerability questionnaires showed a small but significant improvement from baseline in diarrhoea with the reduction in darunavir dose (Figure 2, P = 0.01). Figure 2. View largeDownload slide Changes from baseline in the self-reported gastrointestinal symptom score (higher score was associated with worse symptoms). Only changes from baseline in diarrhoea score significantly improved (P = 0.01). Figure 2. View largeDownload slide Changes from baseline in the self-reported gastrointestinal symptom score (higher score was associated with worse symptoms). Only changes from baseline in diarrhoea score significantly improved (P = 0.01). No patient died during the study. The two pregnant women who switched back to darunavir/r 800/100 mg delivered healthy non-HIV-infected babies. The overall incidence of laboratory abnormalities was low, with most being grade 1 or 2 in severity, and only 14 patients experienced grade 2 or worse laboratory abnormalities, with two grade 3 events (one episode of neutropenia and one episode of ALT elevation) (Table 3). The most frequently reported treatment-emergent grade 2–3 laboratory abnormalities were neutropenia, hyperglycaemia and lipid abnormalities. Changes from baseline to week 48 in fasting lipid-related laboratory parameters (total cholesterol, HDL and LDL cholesterol and triglycerides), glycaemia and plasma CLCR were minimal and non-significant (data not shown). Discussion The results from this single-arm, Phase II, open-label trial in well-suppressed treatment-experienced patients with no darunavir or NRTI RAMs and no previous virological failure demonstrated that over 48 weeks of treatment a switch from once-daily darunavir/r 800/100 mg to darunavir/r 400/100 mg with the same two NRTIs was associated with a high rate of virological suppression of 91.6%. Patients enrolled in the ANRS 165 Darulight study had a long history of treatment with a median of 46 months of antiretroviral therapy, were virologically suppressed for a median of 35 months and had high CD4 cell counts at baseline. These results are consistent with a subset analysis of the POWER 1 and 2 studies in patients with HIV strains susceptible to darunavir, which showed similar virological response rates with once-daily darunavir/r 400/100 and 800/100 mg (78% and 74%, respectively, at week 24).28–29 In addition, clinical trials of darunavir/r in PI-naive or -experienced patients have shown no correlation between PK exposure to darunavir and plasma HIV RNA suppression, when HIV-1 was susceptible to darunavir, suggesting that the optimal dose of darunavir in patients with a susceptible strain is as yet unknown.30,31 It is also reassuring that preliminary PK data reported from the ANRS 165 Darulight study showed a similar AUC of darunavir at the dose of 800/100 or 400/100 mg, with an increase in ritonavir AUC with the low darunavir dose probably because of lower induction on ritonavir.27 In addition, two small pilot studies have also reported high virological suppression rates of 88.5%–90% in patients using once-daily darunavir/r at the 600/100 mg dose.15–16 This strategy of low-dose boosted PIs has also been successful with another PI (atazanavir) in the setting of a large randomized trial, and it would be interesting to confirm the efficacy of the low-dose darunavir/r 400/100 mg in a randomized trial.14 Such a trial is currently ongoing in South Africa (NCT02671383) evaluating, in well-suppressed patients on a PI-based second-line therapy with lopinavir/ritonavir, the non-inferiority of a switch to darunavir/r (400/100 mg) + two NRTIs. Should this trial confirm our findings, this strategy could lead to significant savings for second-line therapy in low- and middle-income countries. In addition, some tolerability benefits could be also associated with this reduced dose, as shown in our study, with a slight reduction in self-reported diarrhoea. Our study has, however, a number of limitations. It was an open-label, non-randomized, one-arm study, with a limited follow-up of only 48 weeks and a limited number of patients enrolled. As such, this trial could not be considered as providing a definite answer regarding the benefit of this dose reduction strategy, which will require evidence based on ongoing Phase III randomized studies. In addition, although the overall success rate was >80%, 6/95 patients (6.3%) experienced virological failure over the first 48 weeks of follow-up and two additional patients did so during extended follow-up, all of whom were fully suppressed at baseline. This rate of virological failure is, however, consistent with previous darunavir/r switch trials in well-suppressed patients. In the MONET trial, 7/129 (5.4%) patients randomized in the darunavir/r + two NRTIs arm experienced a confirmed plasma HIV RNA level >50 copies/mL during follow-up, but the treatment was not changed and at the end of 48 weeks only one patient had a plasma HIV RNA level >50 copies/mL.32 In the ANRS MONOI trial, only 81% of patients randomized to the triple arm of darunavir/r + two NRTIs had sustained plasma HIV RNA levels <50 copies/mL at week 48.33 In the SPIRIT study (Switching boosted Protease Inhibitor to Rilpivirine in combination with Tenofovir/emtricitabine), the rate of virological failure >50 copies/mL in the boosted PI arm was 5% at week 24.34 Because these low levels of plasma HIV RNA replication in patients with regimens based on boosted PIs rarely select for drug RAMs due to the high genetic barrier for the development of resistance to boosted PIs, a number of trials with boosted PIs used a higher plasma HIV RNA threshold to define virological failure, ranging from 200 to 400 copies/mL.14,33 Indeed, in our study over the 72 weeks of follow-up only three of eight patients with plasma HIV RNA >50 copies/mL had a plasma viral load >200 copies/mL and none had emerging NRTI or PI RAMs. Interestingly, the only risk factor for a plasma HIV RNA >50 copies/mL during follow-up was a viral load above the assay threshold at baseline or screening, suggesting that these patients did not have full suppression of viral replication. Nevertheless, this rate of virological failure at 48 weeks in our study seems higher than that reported in more recent switch trials with single-tablet cobicistat-boosted darunavir/tenofovir/emtricitabine in the EMERALD study (2.1% virological failure), or in the STRATEGY-PI trial, where patients maintaining a ritonavir-boosted PI regimen had a 1.4% rate of virological failure, and the results of well-powered randomized trials with low-dose darunavir/r are awaited.4,35 In addition, our results could not be extrapolated to the combination of darunavir with cobicistat because a PK study has reported a 30% reduction in darunavir Cmin levels when boosted with cobicistat as compared with ritonavir, which represents another limitation of our findings because darunavir is now coformulated with cobicistat.36 In conclusion, our pilot study suggests that among well-suppressed patients under a once-daily darunavir/r-based regimen at the standard dose of 800/100 mg with two NRTIs, with no previous virological failure and no darunavir or NRTI RAMS, a switch to a reduced dose of darunavir/r (400/100 mg) is associated with a high rate of virological suppression through to 48 weeks and has a favourable safety and tolerability profile. These results need confirmation in a large randomized trial before this reduced dose of darunavir/r can be recommended in clinical practice. Acknowledgements We thank the patients for their participation and support during the study. We thank Samir Messaoudene for help in conducting the study. We also thank Soizic Le Mestre and Severine Gibowski from ANRS for their help in implementing the study. ANRS 165 Darulight data were previously presented at the 9th International AIDS Society Conference on HIV Science, 23–26 July 2017, Paris, France (abstract MOPEB0313). Members of the ANRS 165 Darulight Study Team The ANRS 165 Darulight study team included the following investigators and co-investigators not listed among the authors: Hopital Saint-Louis, Paris: Dr D. Ponscarme, Dr C. Lascoux; Hopital Saint-Antoine, Paris: Prof. P. M. Girard; Hopital Lariboisière, Paris: Dr A. Rami; Hopital Bichat, Paris: Prof. Y. Yazdanpanah; Hopital Pitié Salpétrière, Internal Medicine: Dr A. Simon; Hopital Pitié Salpêtrière, Infectious Diseases: Dr R. Tubiana; Hopital Pasteur-Necker: Dr C. Duvivier; Hopital Jean Verdier, Bondy: Dr V. Jeantils; Hopital de Nimes: Dr D. Loreillard; Hopital Ste Marguerite, Marseille: Dr I. Poizot-Martin; CHU de Tours: Prof. L. Bernard, Dr G. Gras; CHU de Nantes: Dr C. Allavena, Dr C. Bernaud, Dr S. Bouchez, Dr N. Hall, Dr V. Reliquet, Prof. F. Raffi. Members of the DSMB included: Dr P. De Truchis, I. Charreau, Dr L. Bocquet, Prof. V. Lemoing and G. Point. Members of the scientific committee included: Prof. J. M. Molina, Prof. S. Chevret, E. M. El Abbassi, Dr S. Gallien, Prof. P. Tattevin, Dr G. Gras, Dr M. L. Chaix, Dr G. Peytavin, J. Saillard, S. Couffin-Cadiergues, I. Madelaine, A. Diallo and S. Gibowski. Funding The ANRS 165 Darulight study was funded by ANRS (French National Agency for Research on AIDS and viral hepatitis). Transparency declarations J-M. M. has participated in advisory boards for Gilead, Merck, Janssen, ViiV, Bristol Myers Squibb and Teva, and his institution has received grants from Merck and Gilead. S. G. has received travel grants or honoraria from Gilead Sciences, Janssen and Merck, and his institution has received grants from Pfizer. F. R. has received research funding or honoraria from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, ViiV and Healthcare. P. D. has received travel grants from Bristol Myers Squibb, Janssen and Merck, and his institution has received grants from ViiV Healthcare.  The remaining authors have none to declare. Author contributions All authors contributed to critical revision of the paper for important intellectual content and provided final approval of the version to be published. Substantial contributions to acquisition of data were made by the following authors in their role as principal investigators at their study site: J.-M. M. (Paris, Saint-Louis); S. G. 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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Jun 1, 2018

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