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Dual Raltegravir–Darunavir/Ritonavir Combination in Virologically Suppressed HIV-1-Infected Patients on Antiretroviral Therapy Including a Ritonavir-Boosted Protease Inhibitor Plus Two Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Dual Raltegravir–Darunavir/Ritonavir Combination in Virologically Suppressed HIV-1-Infected... Dual Raltegravir–Darunavir/Ritonavir Combination in Virologically Suppressed HIV-1-Infected Patients on Antiretroviral Therapy Including a Ritonavir-Boosted Protease Inhibitor Plus Two Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors 1 1 1 1 Leonardo Calza , Ilaria Danese , Eleonora Magistrelli , Vincenzo Colangeli , 1 2 2 3 Roberto Manfredi , Isabella Bon , Maria Carla Re , Matteo Conti and Pierluigi Viale Department of Medical and Surgical Sciences, Clinics of Infectious Diseases, “Alma Mater Studiorum” University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy, Microbiology Unit, “Alma Mater Studiorum” University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy, Centralized Laboratory, “Alma Mater Studiorum” University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy Background: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class. Methods: We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks. Results: As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (−85.2 mg/dL), in the prevalence of tubular proteinuria (−56%) and in the mean level of interleukin-6 (−0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events. Conclusion: In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism. Keywords: raltegravir, darunavir, dual therapy, protease inhibitor, switch 1,2 immunodeficiency virus-1 (HIV-1) infection. This Introduction combination antiretroviral therapy (cART) has led to a The combination of two nucleoside/nucleotide reverse remarkable reduction in the acquired immunodeficiency transcriptase inhibitors (NRTIs) plus a non-nucleoside 3,4 syndrome (AIDS)-related morbidity and mortality, but reverse transcriptase inhibitor (NNRTI), a ritona- this treatment is unable to eradicate the HIV infection. vir-boosted protease inhibitor (PI) or an integrase Because the antiretroviral treatment is currently expected strand-transfer inhibitor (INSTI) is the currently rec- to be lifelong, there are increasing concerns about long- ommended initial therapy for patients with human term toxicity, adherence, and cost burden. In particular, some NRTIs have the potential for long- Correspondence to: Leonardo Calza, Department of Medical and Surgical Sciences, Clinics of Infectious Diseases, “Alma Mater Studiorum” term toxicities. For instance, several retrospective and University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. Email: prospective cohort studies have shown an increased risk leonardo.calza@unibo.it © 2016 Taylor & Francis 38 DOI 10.1080/15284336.2015.1122874 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy of renal and bone abnormalities associated with the pro- no regular clinical or laboratory data of follow-up for at longed exposure to the fixed-dose combination tenofovir/ least 48 weeks, active opportunistic diseases or severe emtricitabine, which is the cornerstone of initial antiret- infectious diseases, acute or chronic inflammatory dis- 5–8 roviral therapy. To avoid the long-term NRTI-related eases, alcohol or drug abuse, hypothyroidism, Cushing’s toxicity, several antiretroviral combinations that do not syndrome, acute or chronic kidney diseases, acute hepa- contain NRTIs have been investigated, including dual titis, chronic hepatitis B virus (HBV) or hepatitis C virus regimens based on a ritonavir-boosted PI plus an INSTI. (HCV) infection, liver cirrhosis, myopathy, alanine ami- Darunavir is a potent PI which has shown a durable effi - notransferase (ALT) or aspartate aminotransferase (AST) cacy in both antiretroviral-naïve and experienced patients, >80 U/L, creatine kinase (CK) >170 U/L, pregnancy, an in association with a good tolerability. Raltegravir is the underlying treatment with corticosteroids, anti-inflamma - first-approved INSTI, results in a rapid reduction of HIV tory, immune-modulatory agents, lipid-lowering drugs, viral load in combination with other antiretroviral agents, or a concomitant administration of medications or herbal and has a favorable safety profile. Therefore, a dual com- supplements known to affect the darunavir/ritonavir or bination including darunavir/ritonavir plus raltegravir raltegravir pharmacokinetics (such as the St. John’s Wort). could offer the double advantage of a potent antiretroviral Current alcohol use and intravenous drug dependence regimen without the potential toxicities of the NRTI-based were defined as a daily alcohol consumption >30 g and ≥1 regimens, such as a possible renal and bone damages. intravenous drug use within six months before starting the Dual therapy based on raltegravir in combination with dual regimen, respectively. Liver cirrhosis was excluded a ritonavir-boosted PI has been evaluated with not fully by liver biopsy or elastometry. The HBV and HCV coin- satisfactory results for the treatment of the antiretrovi- fections were diagnosed by the persistent positivity of ral-naïve HIV-1-infected patients (in particular for those HBs antigen or HCV serum antibodies associated with with baseline CD4 lymphocyte count <200 cells/mm HCV-RNA positivity. 11,12 and HIV RNA > 100,000 copies/mL). However, clin- The following demographic, clinical, and laboratory ical data about the use of this dual regimen as a simplifi- data were recorded at the start of therapy and at 12-week cation strategy in treatment-experienced subjects are very intervals during the 48-week follow-up: sex, age, race, limited to date. physical examination, body mass index (BMI), arterial In the present, observational, prospective study we pressure, clinical manifestations, current, and past med- evaluate the effectiveness of a simplification to the dual ications; spot urinalysis, estimated glomerular filtration regimen including raltegravir plus darunavir/ritonavir in rate (eGFR) and serum levels of triglycerides, total a group of HIV-1-infected patients on a stable cART con- cholesterol, low-density lipoprotein (LDL) cholesterol, taining two NRTIs plus one ritonavir-boosted PI and with high-density lipoprotein (HDL) cholesterol, glucose, a persistently suppressed plasma HIV viral load. complete liver and kidney function tests, CK, aldolase, CD4+ and CD8+ T lymphocyte count, and HIV viral Methods load. Patients with proteinuria on spot urines underwent We performed a prospective cohort analysis of HIV- proteinuria and albuminuria (by protein electrophoresis) 1-infected adult patients referring to our Clinics on 24-h collected urines. The eGFR was calculated using of Infectious Diseases from January, 2011 through the four-variable Modification of Diet in Renal Disease December, 2012 receiving a stable antiretroviral regi- (MDRD) formula. men for at least 12 months including a ritonavir-boosted All the plasma samples were analyzed for HIV- PI plus two NRTIs and with persistently undetectable RNA level using the automated COBAS AmpliPrep plasma HIV viral load (HIV RNA < 50 copies/mL) Instrument for specimen processing and the COBAS for at least 6 months. All patients who switched to TaqMan Analyzer for amplification and detection (Roche a dual antiretroviral regimen constituted by ralte- CobasAmpliPrep/Cobas TaqMan HIV-1 tests version 2.0; gravir (400 mg twice daily) and darunavir/ritonavir Roche Diagnostics, Mannheim, Germany). Besides gag (800/100 mg daily) were enrolled in the study and fol- primers and a FAM-labeled gag probe, additional LTR lowed-up for 48 weeks. primers and a FAM-labeled LTR probe were included in Exclusion criteria were current antiretroviral regi- the assay. The two targets, gag and LTR, are amplified men including raltegravir or darunavir/ritonavir, prior with the same efficiency and the limit of quantification exposure to raltegravir or other integrase inhibitors or (LOQ), as defined by the manufacturer, was reduced to darunavir/ritonavir, previous virological failure during a 20 copies/mL. PI-based treatment, previous genotypic testing showing Viral blip was defined as an isolated plasma HIV reduced sensitivity to raltegravir or darunavir/ritonavir, RNA ≥ 20 copies/mL followed by a return to virologic HIV Clinical Trials 2016 VOL. 17 NO. 1 39 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy suppression (<20 copies/mL). Virologic failure was The adherence to the current therapy was carefully defined by a confirmed plasma HIV RNA ≥ 20 copies/mL. checked on the outpatient visits by self-reported question- The following serum markers of inflammation and naires. The study was approved by the Ethic Committee endothelial activation were evaluated: high-sensitivity of the S. Orsola-Malpighi Hospital and all participants C-reactive protein (hsCRP), interleukin-6 (IL-6), and signed an informed consent after receiving information tumor necrosis factor-α (TNF-α). HsCRP was meas- about the purpose of the study. ured by immunonephelometry on an IMMAGE analyzer (Beckman-Coulter, Villepinte, France). IL-6 and TNF-α Results were measured with a sandwich immunological assay Study inclusion criteria were met by 82 patients who were by an EVIDENCE analyzer (Medical Systems, Genova, enrolled in the study. Mean age was 45.2 years, 60 (73%) Italy). The bone health was assessed by a whole-body patients were males, mean current CD4+ lymphocyte DXA scanning (Hologic, QDR 4500A) performed at count was 679 cells/mm , mean duration of current baseline and at week 48 to evaluate total body, subtotal antiretroviral treatment was 4.6 years, and mean duration (total minus head), lumbar spine, and femoral neck bone of plasma HIV RNA < 50 copies/mL was 46.2 months. mineral density (BMD). The lipid parameters were generally abnormal (mean Darunavir/ritonavir therapy was administered by tablets total cholesterol, 258.2 mg/dL; mean triglycerides, at the standard dose of 800/100 mg once daily at break- 286.4 mg/dL). A significant percentage of patients showed fast time and after a standardized continental breakfast. abnormal proteinuria (35.4%), represented mostly by Raltegravir was swallowed by tablets at the standard dose tubular proteinuria (30.5%). Demographic, clinical, and of 400 mg twice daily at breakfast time and at supper- laboratory characteristics of study patients are summarized time. We have assessed the trough plasma concentration in Table 1. (C ) of darunavir, ritonavir, and raltegravir, which is the Current antiretroviral therapy included tenofovir/ trough standard parameter used to define the therapeutic range emtricitabine, abacavir/lamivudine or zidovudine/lami- of these drugs. The C of darunavir, ritonavir, and vudine plus lopinavir/ritonavir, and atazanavir/ritonavir trough raltegravir was assessed at steady state (>4 weeks after or fosamprenavir/ritonavir. The reasons for switch to treatment initiation), with blood samples obtained before raltegravir plus darunavir/ritonavir were renal toxicity the morning dose and 23–25 h after the previous morning (increased creatinine, hypophosphoremia, or tubular dose of darunavir/ritonavr and 11–13 h after the previous proteinuria), reduced BMD, hyperlipidemia, gastrointes- evening dose of raltegravir. The exact times of the predose tinal symptoms, or resistance to nucleoside/nucleotide sample and of the previous morning or evening intake analogues. Current antiretroviral regimens and rea- were recorded, in order to ensure accurately timed blood sons for switching treatment are presented in Table 2. sampling. C was considered to be within an accept- Particularly, all patients with increased creatinine, reduced trough able sampling timeframe if it falls within a defined time phosphoremia, or tubular proteinuria were receiving the range for darunavir every 24 h within 23–25 h after the tenofovir/emtricitabine backbone. last dose and for raltegravir every 12 h within 11–13 h In patients with resistance to NRTIs a previously per- after the last dose. formed genotypic resistance test had shown the pres- The laboratory procedures to evaluate the raltegravir, ence of ≥1 mutations in the reverse transcriptase gene darunavir, and ritonavir C are listed in the Appendix 1. associated with the resistance to ≥1 NRTIs (M184V in 6 trough Treatment failure was defined by virological failure patients, M184V + L74V in 4 patients, M184V + D67N or permanent discontinuation of either one of the two in 2 patients, and M41L + D67N in one patient). These antiretroviral drugs. Genotypic testing was performed resistance patterns did not confer a full resistance to cur- in case of virological failure. Virological success was rent NRTI backbone (tenofovir/emtricitabine in all the 13 defined as a HIV RNA < 20 copies/mL on the study patients), so all patients were virologically suppressed. dual regimen at the end of the 48-week follow-up with After 48 weeks from the switch to raltegravir plus no more than one viral blip. Results were evaluated darunavir/ritonavir, 6 discontinuations were observed: 2 both in intention-to-treat (ITT) and per-protocol (PP) discontinuations due to virological failure and 4 discontin- analyses. The ITT analysis included all subjects who uations due to non-serious adverse events. Overall, viro- switched to the dual regimen raltegravir plus darunavir/ logical success at week 48 was 92.7% in the intent-to-treat ritonavir and were enrolled into the study, while the PP analysis and 97.6% in the per-protocol analysis (Table 3). analysis included all the ITT patients except those who The first case of virological failure was observed at week discontinued the dual regimen for reasons other than 12 (HIV RNA rebound to 4,560 copies/mL) in a patient a virological failure. Missing data were considered as who had been virologically suppressed for 38 months failures. with a regimen including tenofovir/emtricitabine plus 40 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy Table 1 Baseline characteristics of the 82 patients enrolled in the study No. of patients 82 Males, No. (%) 60 (73.2) White subjects, No. (%) 78 (95.1) Age (years), mean (SD) 45.2 (18.7) HIV transmission risk category, No. (%) • IDU 16 (19.5) • MSM 36 (43.9) • Heterosexual 30 (36.6) CD4+ cell count nadir (cells/mm ), mean (SD) 219 (52) Current CD4+ lymphocyte count (cells/mm ), mean (SD) 679 (167) Duration of HIV infection (years), mean (SD) 8.3 (3.9) Duration of current ARV therapy (years), mean (SD) 4.6 (2.2) Cumulative exposure to ARV therapy (years), mean (SD) 7.9 (3.4) Duration of plasma HIV RNA < 50 copies/mL with current ARV therapy (months), mean (SD) 46.2 (18.5) Total cholesterol (mg/dL), mean (SD) 258.2 (62.4) LDL cholesterol (mg/dL), mean (SD) 147.5 (29.7) HDL cholesterol (mg/dL), mean (SD) 46.2 (15.2) Triglycerides (mg/dL), mean (SD) 286.4 (89.7) Creatinine (mg/dL), mean (SD) 1.07 (0.59) eGFR (mL/min/1.73 m ), mean (SD) 79.2 (14.6) Phosphorus (mg/dL), mean (SD) 2.61 (0.69) Patients with proteinuria >30 mg/dL, No. (%) 29 (35.4) Patients with tubular proteinuria, No. (%) 25 (30.5) BMD • Total body (g/cm ), mean (SD) 0.933 (.192) • Subtotal (g/cm ), mean (SD) 0.715 (.148) • Lumbar spine (g/cm ), mean (SD) 0.855 (.102) • Femoral neck (g/cm ), mean (SD) 0.779 (0.121) hs-CRP (mg/dL), mean (SD) 0.13 (0.11) IL-6 (pg/mL), mean (SD) 3.9 (2.5) TNF-α (pg/mL), mean (SD) 14.7 (8.5) Notes: SD, standard deviation; IDU, intravenous drug users; MSM, men who have had sex with men; ARV, antiretroviral; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate by four-variable Modification of Diet in Renal Disease (MDRD) formula ; BMD, bone mineral density; hs-CRP, high sensitivity C-reactive protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α. Table 2 Current antiretroviral treatment at the moment of the switch and reasons for switching treatment to raltegravir plus darunavir/ritonavir Current NRTIs, no (%) • Tenofovir + emtricitabine 51 (62.2) • Abacavir + lamivudine 27 (32.9) • Zidovudine + lamivudine 4 (4.9) Current PIs, No. (%) • Lopinavir/ritonavir 51 (62.2) • Atazanavir/ritonavir 20 (24.4) • Fosamprenavir/ritonavir 11 (13.4) Reasons for discontinuation • Increased creatinine, No. (%) 21 (25.6) • Hypophosphoremia, No. (%) 26 (31.7) • Tubular proteinuria, No. (%) 25 (30.5) • Reduced BMD, No. (%) 15 (18.3) • Hyperlipidemia, No. (%) 54 (65.8) • Gastrointestinal symptoms, No. (%) 41 (50) • Resistance to NRTIs, No. (%) 13 (15.8) Notes: NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; BMD, bone mineral density. atazanavir/ritonavir. The second case of virological failure adherence to cART was lower than 95% and genotypic was observed at week 24 (HIV RNA rebound to 810 cop- analysis at the time of virological failure demonstrated no ies/mL) in a patient who had been virologically suppressed resistance mutations. for 29 months with a regimen including abacavir/lamivu- The C of darunavir, ritonavir, and raltegravir was trough dine plus lopinavir/ritonavir. In both cases, the patient’s low in both patients with virological failure, confirming HIV Clinical Trials 2016 VOL. 17 NO. 1 41 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy Table 3 Immunological, virological, and biological results after the switch to raltegravir plus darunavir/ritonavir Week 24 p value Week 48 p value Treatment failures, No. (%) • Discontinuations do to AE 3 (3.7) 0.912 4 (4.9) 0.681 • Virological failures 41 (1.2) 0.774 2 (2.4) 0.439 • Loss to follow-up or missing data or 0 0 withdrew consent Virological successes, No. (%) • HIV RNA < 20 copies/mL (ITT analysis) 78 (7895.1) 0.387 76 (92.7) 0.448 • HIV RNA < 20 copies/mL (PP analysis) 81 (98.8) 0.709 80 (97.6) 0.379 Median change from baseline in CD4+ +31 (−4,+63) 0.311 +65 (+11,+101) 0.042 lymphocyte count (cells/mm ) (95% CI) Median change from baseline in serum lipids (mg/dL), (95% CI): • Total cholesterol −44.5 (−17.6,−72.5) 0.067 −37.6 (−11.5,−66.8) 0.098 • LDL cholesterol −20.6 (−5.5,−37.1) 0.089 −22.5 (−2.5,−40.1) 0.102 • HDL cholesterol +3.2 (+0.9,+5.1) 0.328 +2.8 (+0.4,+4.4) 0.562 • Triglycerides −91.4 (−42,−135) 0.012 −85.2 (−49,−126) 0.017 Median change from baseline in creatinine −0.04 (+0.02,−0.11) 0.523 −0.02 (+0.03,−0.09) 0.871 (mg/dL), (95% CI) Median change from baseline in eGFR (mL/ +2.4 (+1.1,+3.9) 0.387 +1.5 (+0.6,+3.1) 0.721 min/1.73 m ), (95% CI) Median change from baseline in phospho- +0.64 (+0.17,+0.93) 0.023 +0.58 (+0.11,+0.84) 0.031 rus (mg/dL), (95% CI) Patients with tubular proteinuria, No. (%) 19 (24.4) 11 (14.5) Change in No. of patients with tubular −6 (−24%) 0.013 −14 (−56%) 0.003 proteinuria (%) Median change from baseline in BMD (%) • Total body, mean (95% CI) −1.2 (+0.4,−1.6) 0.491 −1.3 (+0.3,−1.8) 0.792 • Lumbar spine, mean (95% CI) −1.1 (+0.5,−1.5) 0.672 −1.3 (+0.6,−1.6) 0.641 • Femoral neck, mean (95% CI) −1.3 (+0.4,−1.7) 0.581 −1.4 (+0.4,−1.6) 0.669 Median change from baseline in inflamma- tory markers • hs-CRP (mg/dL), mean (95% CI) −0.02 (−0.05,+0.01) 0.388 −0.03 (−0.06,+0.01) 0.576 • IL-6 (pg/mL), mean (95% CI) −0.97 (−1.23,−0.65) 0.021 −0.94 (−1.29,−0.58) 0.018 • TNF-α (pg/mL), mean (95% CI) −1.52 (−2.23,−0.98) 0.082 −1.33 (−2.09,−0.87) 0.792 Notes: AE, adverse event; ITT, intent-to-treat; PP, per protocol; CI, confidence interval; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate by four-variable Modification of Diet in Renal Disease (MDRD) formula ; BMD, bone mineral density; hs-CRP, high sensitivity C-reactive protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α. a poor adherence to current cART (1,205, 154, and subtotal, lumbar spine, and femoral neck) were not signif- 37 ng/ mL, respectively, in the first patient; 1,309, 172, icant. There was a significant increase in the mean serum and 42 ng/mL, respectively, in the second patient). phosphorus concentration both at week 24 (+0.64 mg/dL; The four discontinuations for non-serious adverse p = 0.023) and at week 48 (+0.58 mg/dL; p = 0.031), and events were due to diarrhea with abdominal discomfort a significant decrease in the prevalence of tubular pro- in three cases and nausea with lack of appetite in one case. teinuria both at week 24 (−24%; p = 0.013) and at week All the immunological, virological, and biological 48 (−56%; p = 0.003). results at week 24 and at week 48 after the switch are Changes in mean serum phosphorus level and preva- summarized in Table 3. lence of tubular proteinuria in patients switching from a The median increase in the CD4+ T lymphocyte count tenofovir/emtricitabine backbone are reported in Table 4. from baseline to week 48 was statistically significant With regard to the inflammation markers, a signifi- (+65 cells/mm ; p = 0.042). The change in mean serum cant reduction in the mean concentration of IL-6 both concentration of triglycerides showed a statistically signif- at week 24 (−0.97 pg/mL; p = 0.021) and at week 48 icant reduction both at week 24 (−91.4 mg/dL; p = 0.012) (−0.94 mg/ dL; p = 0.018) was reported, while changes and at week 48 (−85.2 mg/dL; p = 0.017). There was in mean levels of hs-CRP and TNF-α were not significant. also a reduction in total and LDL cholesterol levels, but No serious adverse events were reported during the it was not statistically significant, such as the increase in 48-week follow-up. No grade 3 or 4 clinical events or the HDL cholesterol level. The variations in mean values laboratory abnormalities were recorded during the study. of serum creatinine, eGFR, and BMD (both total body, The most common adverse events reported during the 42 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy Table 4 Changes in renal function parameters in the subset of 51 patients switching from tenofovir/emtricitabine plus a ritonavir boosted-protease inhibitor to raltegravir plus darunavir/ritonavir Week 24 p value Week 48 value Median change from baseline in creatinine (mg/dL), (95% CI) −0.05 (+0.03,−0.13) 0.112 −0.03 (+0.05,−0.11) 0.322 Median change from baseline in eGFR (mL/min/1.73 m ), (95% CI) +2.2 (+1.3,+3.7) 0.522 +1.7 (+0.4,+3.4) 0.401 Median change from baseline in phosphorus (mg/dL), (95% CI) +0.68 (+0.21,+0.97) 0.017 +0.64 (+0.17,+0.89) 0.009 Patients with tubular proteinuria, No. (%) 19 (37.2) 11 (21.6) Change in No. of patients with tubular proteinuria (%) −6 (−24%) 0.013 −14 (−56%) 0.003 Notes: CI, confidence interval; eGFR, estimated glomerular filtration rate by four-variable Modification of Diet in Renal Disease (MDRD) formula . median value (and range) for ritonavir C was 308 trough (154–479) ng/mL. Between and within variability of the ritonavir plasma C were 44% and 69%, respectively. trough The mean C of raltegravir was 94 ng/mL (95% CI, trough 55, 149), and the median value (and range) for raltegra- vir C was 132 (37–221) ng/mL. Between and within trough variability of the raltegravir plasma C were 82% and trough 108%, respectively (Figure 2). Between and within varia- bility of the raltegravir C were higher than those of the trough darunavir and ritonavir C , but the raltegravir concen- Figure 1 Darunavir plasma concentration. Box plot trough definition: the horizontal bar represents the mean; the box tration was above the recommended minimum effective represents the 95% confidence interval (95% CI); vertical bars concentration (15 ng/mL) in all the evaluated subjects. represent values between upper and lower limit; squares Overall, the adherence to the antiretroviral treatment represent outliers. was ≥95% in 72 out of 82 (87.8%) enrolled patients and in 70 out of 76 (92.1%) patients who completed the study. All the remaining patients had a treatment adherence ≥80%. Discussion A dual therapy based on raltegravir in combination with a ritonavir-boosted PI has been investigated mostly in antiretroviral-naïve HIV-positive subjects, while data regarding this NRTI-sparing combination as simplification strategy in antiretroviral-experienced subjects are lacking still today. In particular, raltegravir has been evaluated in Figure 2 Raltegravir plasma concentration. Box plot association with lopinavir/ritonavir, atazanavir/ritonavir, definition: the horizontal bar represents the mean; the box or darunavir/ritonavir. represents the 95% confidence interval (95% CI); vertical bars The PROGRESS study was a randomized, open- represent values between upper and lower limit; squares represent outliers. label study comparing lopinavir/ritonavir (400/100 mg twice daily) in association with tenofovir/emtricitabine (300/200 mg once daily) or raltegravir (400 mg twice follow-up were diarrhea with abdominal discomfort daily) in 206 antiretroviral-naïve HIV-1-infected patients. (5 patients; 6.1%), nausea and loss of appetite (3; 3.6%), The virological response (percentage of patients with headache (2; 2.4%), asthenia (2; 2.4%), and a slight HIV RNA < 40 copies/mL) at week 96 was comparable increase (<400 U/L) in the creatine kinase (CK) level (2; in the two treatment groups (66.3% among patients 2.4%). receiving lopinavir/ritonavir plus raltegravir and 68.6% The pharmacokinetic evaluation by the C assess- trough among those receiving lopinavir/ritonavir plus tenofovir/ ment was performed in all the 82 enrolled subjects. emtricitabine), such as the increase in the mean CD4+ The mean C of darunavir was 1,927 ng/mL (95% trough T cell count (281 cells/mm in the lopinavir/ritonavir/ CI, 1,381, 3,362), and the median value (and range) for raltegravir treatment group and 296 cells/mm in the darunavir C was 2,288 (1,205–3,744) ng/mL. Between trough lopinavir/ritonavir/tenofovir/emtricitabine group). The and within variability of the darunavir plasma C were trough safety and tolerability profiles were similar between 37% and 54%, respectively (Figure 1). The mean C trough groups, but the lopinavir/ritonavir/raltegravir regimen of ritonavir was 279 ng/mL (95% CI, 188, 445), and the HIV Clinical Trials 2016 VOL. 17 NO. 1 43 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy led to a statistically significant greater increase in the ritonavir (800/100 mg daily) plus raltegravir (400 mg peripheral fat from baseline to week 96. Moreover, twice daily) or tenofovir/emtricitabine (300/200 mg subjects treated with lopinavir/ritonavir plus raltegravir daily). After a 96-week follow-up, the NRTI-sparing showed a significantly greater increase in total bone treatment was found to be non-inferior to standard treat- mineral density and a significantly smaller decrease in ment. The Kaplan–Meier estimated proportion of treat- eGFR in comparison with patients treated with lopinavir/ ment failures and the percentage of patients with HIV ritonavir plus tenofovir/emtricitabine. RNA < 50 copies/mL were, respectively, 17.8% and The dual regimen raltegravir plus lopinavir/ritona- 89.4% in the NRTI-sparing regimen group, and 13.8% and vir was investigated also as a second-line regimen in 93.3% in the standard regimen group. The treatment fail- patients with virological failure. The SECOND-LINE ure risk was significantly higher in subjects with a baseline randomized, open-label trial enrolled 558 patients with CD4 lymphocyte count <200 cells/mm , while a post hoc confirmed plasma HIV RNA > 500 copies/mL after exploratory analysis showed a significantly greater risk ≥24 weeks of first-line treatment who were randomized of treatment failure only in those with both CD4 lym- to receive lopinavir/ritonavir plus two or three NRTIs or phocyte count <200 cells/mm and HIV RNA > 100,000 raltegravir. At 48 weeks, the proportion of subjects with copies/mL at baseline. The immunological response and HIV RNA < 200 copies/mL was comparable in the ral- the frequency of serious and non-serious adverse events tegravir group and in the NRTI group (83% and 81%, were similar in patients treated with NRTI-sparing or respectively), with a good safety profile in both groups. standard regimen, even though subjects treated with In a substudy of this trial, the raltegravir-based combina- darunavir/ritonavir plus tenofovir/emtricitabine showed a tion led to a similar improvement in limb fat but a worse significantly greater decrease in the creatinine clearance. total:HDL cholesterol ratio after 48 weeks in comparison On the contrary, this dual regimen showed a worse viro- with the NRTI-based regimen. The bone mineral density logical response in the RADAR study. In this randomized, decrease at 96 weeks was greater in patients treated with open-label trial, 85 antiretroviral-naïve adults were ran- the NRTI-based regimen than in those receiving lopinavir/ domized to receive darunavir/ritonavir (800/100 mg ritonavir plus raltegravir. once daily) in association with tenofovir/emtricitabine The effectiveness of the NRTI-sparing and ritona- (300/200 mg once daily) or raltegravir (400 mg twice vir-sparing dual regimen including atazanavir (300 mg daily). At 48 weeks, the percentage of patients with HIV twice daily) plus raltegravir (400 mg twice daily) was RNA < 48 copies/mL by the intention-to-treat analysis evaluated in the randomized, open-label SPARTAN study. was significantly lower in the raltegravir group than in the Ninety-three antiretroviral-naïve patients were rand- NRTI group (62.5% versus 83.7%, respectively), while omized to receive atazanavir plus raltegravir or atazanavir/ changes in the CD4+ T lymphocyte count, total choles- ritonavir (300/100 mg daily) plus tenofovir/emtricitabine terol/HDL cholesterol ratio, and eGFR were compara- (300/200 mg daily). After a 24-week follow-up, the pro- ble between groups. However, in patients treated with portion of patients with HIV viral load <50 copies/mL raltegravir changes in subtotal bone mineral density and was comparable in the atazanavir–raltegravir group and markers of bone metabolism were more favorable than in in the atazanavir/ritonavir/tenofovir/emtricitabine group those receiving tenofovir/emtricitabine. (74.6% and 63.3%, respectively), while both safety profile A possible lower antiviral effect of the darunavir/ and resistance risk of the experimental regimen did not ritonavir combined with raltegravir has been proposed appear satisfactory. based on a potential unfavourable pharmacokinetic The efficacy and safety of raltegravir in combina - interaction between these drugs, leading to reduced tion with darunavir/ritonavir was investigated in the darunavir plasma concentrations. However, pharma- ACTG 5262 and in the NEAT001/ANRS143 studies. cokinetic data about this potential interaction are still In the ACTG 5262 single-arm, multicenter study, 112 limited and controversial. antiretroviral-naïve patients received darunavir/ritonavir A pharmacokinetic study evaluated the plasma con- (800/100 mg daily) and raltegravir (400 mg twice daily) centrations of darunavir and ritonavir in 53 HIV-infected for 24 weeks. This dual combination was well-tolerated, adult patients with or without concomitant raltegravir but virologic failure and integrase resistance occur- administration. No significant differences were detected rence were common. Particularly, virologic failure rate about the darunavir and ritonavir C in patients receiv- trough was 16% and it was associated with baseline viral load ing or not raltegravir, but the raltegravir co-administration >100,000 copies/mL. led to a 40% reduction in the darunavir maximum con- In the NEAT001/ANRS143 European, multicenter, ran- centration (C ) and the estimate area under the curve max domized, open-label trial, 805 antiretroviral-naïve sub- 0–24 h (AUC ), as well a 60% increase in the estimated 0–24 jects were enrolled and randomized to receive darunavir/ darunavir clearance. 44 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy On the other hand, a pilot, open-label, prospective 92% of patients switching from a triple therapy including study showed a favorable pharmacokinetic profile for a ritonavir-boosted PI plus two NRTIs. This dual regimen this association. In this study, the 24-h pharmacoki- had acceptable tolerance without serious adverse events netics of darunavir and raltegravir was assessed in 15 and led to a significant improvement of some tenofovir- HIV-positive patients taking raltegravir (400 mg twice associated toxic effects, such as the reduced prevalence daily) and darunavir/ritonavir (800/100 mg once daily). of tubular proteinuria and ipophosphoremia. A significant The darunavir and raltegravir AUC , C , and C decrease in the triglyceride serum concentration was also 0–24 max trough were not significantly altered by the co-administration observed, and the patients’ adherence to the dual regimen of these drugs. Particularly, the geometric mean value was ≥95% in the 88% of cases in spite of an asymmetric of the darunavir C was 1330 ng/mL (95% CI, 1110– drug dosage (raltegravir twice daily and darunavir/ritona- trough 1760; IC for wild-type and resistant HIV-1 strains, 55 vir once daily). and 550 ng/mL, respectively) and the geometric mean The evaluation of the darunavir, ritonavir, and ralte- value of the raltegravir C was 40 ng/mL (95% CI, gravir serum concentrations showed that mean, median, trough 30–80). and range values of the C for each drug were within trough Some other NRTI-sparing associations were evaluated the therapeutic range established in previous studies and 1,23 to avoid toxic effects associated with NRTIs. In the ACTG international guidelines. Therefore, the unfavorable 5142-randomized trial, three regimens were compared for pharmacokinetic interaction between raltegravir and initial therapy: efavirenz plus two NRTIs, lopinavir/ritona- darunavir shown in other studies and leading to a signif- vir plus two NRTIs, and lopinavir-ritonavir plus efavirenz. icant decrease in the darunavir plasma exposure was not The virologic efficacy of the NRTI-sparing regimen was observed in our study. similar to that of the triple efavirenz-based combination Our work clearly presents several limitations. First, it and higher than that of the triple lopinavir–ritonavir-based was an observational study with a limited sample size regimen. However, the NRTI-sparing therapy was more and a strict selection of the study population because of likely associated with the drug resistance occurrence. numerous exclusion criteria, hence the conclusions are A dual regimen including lamivudine plus a ritona- not broadly applicable to a standard patient population. vir-boosted PI has been assessed in both antiretrovi- Second, the effectiveness of dual regimen was not com- ral-naïve and antiretroviral-experienced patients. In the pared with the standard NRTI-based triple regimen. In GARDEL-randomized trial, 426 antiretroviral-naïve spite of this, rates of virological suppression were very subjects were randomly assigned to dual therapy high and similar to those observed among subjects receiv- lopinavir/ritonavir plus lamivudine or triple therapy ing triple antiretroviral therapy in randomized clinical 28–30 lopinavir/ritonavir plus two NRTIs (in fixed-dose studies assessing other strategies of simplification. combination). After 48 weeks, virological response Another limitation was the heterogeneity of the triple was similar (also in patients with baseline viral load regimens switched to the raltegravir/darunavir/ritonavir ≥100,000 copies/mL), while toxicity-related discon- combination, that made impossible to assess the improve- tinuations were more common in the triple-therapy ment after the switch in some toxic effects associated with group. In the SALT-randomized study, 286 virologi- specific kinds of NRTIs and boosted PIs. Finally, some cally suppressed patients on stable cART were assigned aspects, such as the control of viral replication in the cen- to dual treatment atazanavir/ritonavir plus lamivu- tral nervous system or other reservoirs and the effect on dine or triple treatment atazanavir/ritonavir plus two the immune activation markers or peripheral fat were not NRTIs. After 48 weeks, dual therapy was found to be evaluated. effective, safe, and non-inferior to triple treatment. In conclusion, despite these limitations, in our study, the A retrospective study evaluated 94 virologically sup- dual therapy containing raltegravir and darunavir/ritonavir pressed treatment-experienced patients who switched was well tolerated after a 48-week follow-up as simpli- to dual regimen darunavir/ritonavir plus lamivudine fication strategy in persistently suppressed HIV-infected and showed a good profile of efficacy and safety after patients and may be particularly attractive for patients a 12-month follow-up. with genotypic resistance to NRTIs or in whom some toxic Our study is the first published work assessing the dual effects associated with the NRTI use have been reported NRTI-sparing regimen containing raltegravir (400 mg or should be avoided. Larger and properly designed ran- twice daily) and darunavir/ritonavir (800/100 mg) as sim- domized studies are certainly requested in order to better plification strategy in antiretroviral-experienced patients. evaluate the effectiveness and the safety of this strategy, This regimen after a 48-week follow-up allowed the main- as well as to better define the selected patients in whom tenance of plasma virological suppression in more than this option is applicable. HIV Clinical Trials 2016 VOL. 17 NO. 1 45 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy lopinavir/ritonavir compared with standard second-line therapy. Disclosure statement J Acquir Immune Defic Syndr. 2014;67:161–168. There are no conflicts of interest to declare. 19. Kozal MJ, Lupo S, DeJesus E, et al. A nucleoside- and ritonavir- sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naïve HIV-infected patients: SPARTAN References study results. 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Curr 2008;358:2095–2106. Opin HIV AIDS. 2011;6:285–289. 25. Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with 6. Maggi P, Bartolozzi D, Bonfanti P, et al. Renal complications in lopinavir and ritonavir plus lamivudine versus triple therapy with HIV disease: between present and future. AIDS Rev. 2012;14:37–53. lopinavir and ritonavir plus two nucleoside reverse transcriptase 7. Calza L. Renal toxicity associated with antiretroviral therapy. HIV inhibitors in antiretroviral-therapy-naïve adults with HIV-1 infection: Clin Trials. 2012;13:189–211. 48 weeks results of the randomized, open-label, non-inferiority 8. Calmy A, Fux CA, Norris R, et al. Low bone mineral density, renal GARDEL trial. Lancet Infect Dis. 2014;14:572–580. dysfunction, and fracture risk in HIV infection: a cross‐sectional 26. Perez-Molina JA, Rubio R, Rivero A, et al. Dual treatment with study. J Infect Dis. 2009;200:1746–1754. atazanavir-ritonavir plus lamivudine versus triple treatment with 9. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and atazanavir-ritonavir plus two nucleos(t)ides in virologically stable safety of once-daily darunavir/ritonavir compared with lopinavir/ patients with HIV-1 (SALT): 48 weeks results from a randomized, ritonavir in HIV-1-infected treatment naïve patients in the ARTEMIS open-label, non-inferiority trial. Lancet Infect Dis. 2015;15:775–784. trial. HIV Med. 2013;14:49–59. 27. Borghetti A, Mondi A, Piccoli B, et al. Switching to lamivudine 10. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and plus darunavir/r dual therapy in a cohort of treatment-experienced safety of raltegravir versus efavirenz when combined with tenofovir/ HIV-positive patients: the experience of an Italian centre. J Int AIDS emtricitabine in treatment-naive HIV-1-infected patients: final Soc. 2014;17:19817. 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 28. Martin A, Bloch M, Amin J, et al. Simplification of antiretroviral 2013;63:77–85. therapy with tenofovir/emtricitabine or abacavir/lamivudine: 11. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted a randomized, 96-week trial. Clin Infect Dis. 2009;49:1591–1601. darunavir combined with raltegravir or tenofovir/emtricitabine in 29. DeJesus E, Young B, Morales-Ramirez JO, et al. Simplification antiretroviral-naïve adults infected with HIV-1: 96 week results from of antiretroviral therapy to a single-tablet regimen consisting of the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. efavirenz, emtricitabine, and tenofovir disoproxil fumarate versus 2014;384:1942–1951. unmodified antiretroviral therapy in virologically suppressed HIV-1- 12. Bedimo RJ, Drechsler H, Jain M, et al. The RADAR study: week 48 infected patients. J Acquir Immune Defic Syndr. 2009;51:163–174. safety and efficacy of raltegravir combined with boosted darunavir 30. Martinez E, Larrousse M, Libre JM, et al. Substitution of raltegravir compared to tenofovir/emtricitabine combined with boosted for ritonavir-boosted protease inhibitors in HIV-infected patients: the darunavir in antiretroviral-naïve patients. Impact on bone health. SPIRAL study. AIDS. 2010;24:1697–1707. PLoS One. 2014;9:e106221. 13. Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study Appendix 1 equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–254. Blood samples were collected in 3.0 mL Vacuette EDTA- 14. Dickinson L, Robinson L, Tjia J, et al. Simultaneous determination of HIV protease inhibitors amprenavir, atazanavir, indinavir, containing tubes and were centrifuged (600 g for 10 min) lopinavir, nelfinavir, ritonavir and saquinavir in human plasma to obtain plasma samples within two hours of collection. by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. The plasma samples were frozen at −20 °C and were sent 2005;829:82–90. on dry ice to the Central Laboratory of the S. Orsola- 15. Reynes J, Trinh R, Pulido F, et al. Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive Malpighi Hospital to assess the antiretroviral drugs’ C . trough subjects: 96-week results of the PROGRESS study. AIDS Res Hum After thawing, HIV was inactivated at 56 °C for 30 min, Retroviruses. 2013;29:256–265. 16. Boyd MA, Kumarasamy N, Moore CL, et al. Ritonavir-boosted then the plasma samples were extracted and subjected lopinavir plus nucleoside or nucleotide reverse transcriptase to a validated high-performance liquid chromatography inhibitors versus ritonavir-boosted lopinavir plus raltegravir for (HPLC)–tandem mass spectrometry method, as devi- treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECON-LINE): a randomized, 14 ations from the method described by Dickinson et al. open-label, non-inferiority study. Lancet. 2013;381:2091–2099. Internal standard (cimetidine) and acetonitrile (400 μL) 17. Martin A, Moore CL, Mallon PW, et al. HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2–3 were added to aliquots (100 μL) of calibrators, quality nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or controls, and patient ultrafiltrate. After mixing, cen- LPV/r + raltegravir as second-line antiretroviral therapy. PLoS One. 2013;8:e77138. trifugation, and addition of ammonium formate buffer 18. Haskelberg H, Mallon PW, Hoy J, et al. Bone mineral density over 96 (100 μL; 20 mM), samples were analyzed by HPLC–tandem weeks in adults failing first-line therapy randomized to raltegravir/ 46 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy mass spectrometry (10 μL). Fragmentation of parent the high-QC concentration (10,000 ng/mL). Inter-assay molecules into daughter ions occurred by electrospray coefficients of variation were 9.4% and 9.3% for darunavir ionization; ions were separated according to their m/z ratio and raltegravir, respectively, for the low-QC concentration, and quantified by the intensity of their respective daughter and 8% and 8.5%, respectively, for the high-QC concen- ions. The standard curves for darunavir and raltegravir tration. The corresponding accuracy ranged between 91% were linear within the ranges of 40 ng/mL to 12,000 ng/mL and 102% for darunavir, and 95–109% for raltegravir. in plasma, with a lower limit of detection of 20 ng/mL for The median C of darunavir (at 800 mg daily in asso- trough all drugs. Intra-assay coefficients of variation for darunavir ciation with ritonavir 100 mg daily) and raltegravir from and raltegravir quality control (QC) concentrations were clinical studies were 1,340 and 72 ng/mL, respectively. 9.8% and 9.1%, respectively, for the low-QC concentra- These concentrations have been used as a guideline for tion (60 ng/mL), and 8.1% and 8.9%, respectively, for analyzing the data. HIV Clinical Trials 2016 VOL. 17 NO. 1 47 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png HIV Clinical Trials Taylor & Francis

Dual Raltegravir–Darunavir/Ritonavir Combination in Virologically Suppressed HIV-1-Infected Patients on Antiretroviral Therapy Including a Ritonavir-Boosted Protease Inhibitor Plus Two Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

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Taylor & Francis
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© 2016 Taylor & Francis
ISSN
1528-4336
eISSN
1945-5771
DOI
10.1080/15284336.2015.1122874
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26728706
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Abstract

Dual Raltegravir–Darunavir/Ritonavir Combination in Virologically Suppressed HIV-1-Infected Patients on Antiretroviral Therapy Including a Ritonavir-Boosted Protease Inhibitor Plus Two Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors 1 1 1 1 Leonardo Calza , Ilaria Danese , Eleonora Magistrelli , Vincenzo Colangeli , 1 2 2 3 Roberto Manfredi , Isabella Bon , Maria Carla Re , Matteo Conti and Pierluigi Viale Department of Medical and Surgical Sciences, Clinics of Infectious Diseases, “Alma Mater Studiorum” University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy, Microbiology Unit, “Alma Mater Studiorum” University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy, Centralized Laboratory, “Alma Mater Studiorum” University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy Background: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class. Methods: We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks. Results: As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (−85.2 mg/dL), in the prevalence of tubular proteinuria (−56%) and in the mean level of interleukin-6 (−0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events. Conclusion: In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism. Keywords: raltegravir, darunavir, dual therapy, protease inhibitor, switch 1,2 immunodeficiency virus-1 (HIV-1) infection. This Introduction combination antiretroviral therapy (cART) has led to a The combination of two nucleoside/nucleotide reverse remarkable reduction in the acquired immunodeficiency transcriptase inhibitors (NRTIs) plus a non-nucleoside 3,4 syndrome (AIDS)-related morbidity and mortality, but reverse transcriptase inhibitor (NNRTI), a ritona- this treatment is unable to eradicate the HIV infection. vir-boosted protease inhibitor (PI) or an integrase Because the antiretroviral treatment is currently expected strand-transfer inhibitor (INSTI) is the currently rec- to be lifelong, there are increasing concerns about long- ommended initial therapy for patients with human term toxicity, adherence, and cost burden. In particular, some NRTIs have the potential for long- Correspondence to: Leonardo Calza, Department of Medical and Surgical Sciences, Clinics of Infectious Diseases, “Alma Mater Studiorum” term toxicities. For instance, several retrospective and University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. Email: prospective cohort studies have shown an increased risk leonardo.calza@unibo.it © 2016 Taylor & Francis 38 DOI 10.1080/15284336.2015.1122874 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy of renal and bone abnormalities associated with the pro- no regular clinical or laboratory data of follow-up for at longed exposure to the fixed-dose combination tenofovir/ least 48 weeks, active opportunistic diseases or severe emtricitabine, which is the cornerstone of initial antiret- infectious diseases, acute or chronic inflammatory dis- 5–8 roviral therapy. To avoid the long-term NRTI-related eases, alcohol or drug abuse, hypothyroidism, Cushing’s toxicity, several antiretroviral combinations that do not syndrome, acute or chronic kidney diseases, acute hepa- contain NRTIs have been investigated, including dual titis, chronic hepatitis B virus (HBV) or hepatitis C virus regimens based on a ritonavir-boosted PI plus an INSTI. (HCV) infection, liver cirrhosis, myopathy, alanine ami- Darunavir is a potent PI which has shown a durable effi - notransferase (ALT) or aspartate aminotransferase (AST) cacy in both antiretroviral-naïve and experienced patients, >80 U/L, creatine kinase (CK) >170 U/L, pregnancy, an in association with a good tolerability. Raltegravir is the underlying treatment with corticosteroids, anti-inflamma - first-approved INSTI, results in a rapid reduction of HIV tory, immune-modulatory agents, lipid-lowering drugs, viral load in combination with other antiretroviral agents, or a concomitant administration of medications or herbal and has a favorable safety profile. Therefore, a dual com- supplements known to affect the darunavir/ritonavir or bination including darunavir/ritonavir plus raltegravir raltegravir pharmacokinetics (such as the St. John’s Wort). could offer the double advantage of a potent antiretroviral Current alcohol use and intravenous drug dependence regimen without the potential toxicities of the NRTI-based were defined as a daily alcohol consumption >30 g and ≥1 regimens, such as a possible renal and bone damages. intravenous drug use within six months before starting the Dual therapy based on raltegravir in combination with dual regimen, respectively. Liver cirrhosis was excluded a ritonavir-boosted PI has been evaluated with not fully by liver biopsy or elastometry. The HBV and HCV coin- satisfactory results for the treatment of the antiretrovi- fections were diagnosed by the persistent positivity of ral-naïve HIV-1-infected patients (in particular for those HBs antigen or HCV serum antibodies associated with with baseline CD4 lymphocyte count <200 cells/mm HCV-RNA positivity. 11,12 and HIV RNA > 100,000 copies/mL). However, clin- The following demographic, clinical, and laboratory ical data about the use of this dual regimen as a simplifi- data were recorded at the start of therapy and at 12-week cation strategy in treatment-experienced subjects are very intervals during the 48-week follow-up: sex, age, race, limited to date. physical examination, body mass index (BMI), arterial In the present, observational, prospective study we pressure, clinical manifestations, current, and past med- evaluate the effectiveness of a simplification to the dual ications; spot urinalysis, estimated glomerular filtration regimen including raltegravir plus darunavir/ritonavir in rate (eGFR) and serum levels of triglycerides, total a group of HIV-1-infected patients on a stable cART con- cholesterol, low-density lipoprotein (LDL) cholesterol, taining two NRTIs plus one ritonavir-boosted PI and with high-density lipoprotein (HDL) cholesterol, glucose, a persistently suppressed plasma HIV viral load. complete liver and kidney function tests, CK, aldolase, CD4+ and CD8+ T lymphocyte count, and HIV viral Methods load. Patients with proteinuria on spot urines underwent We performed a prospective cohort analysis of HIV- proteinuria and albuminuria (by protein electrophoresis) 1-infected adult patients referring to our Clinics on 24-h collected urines. The eGFR was calculated using of Infectious Diseases from January, 2011 through the four-variable Modification of Diet in Renal Disease December, 2012 receiving a stable antiretroviral regi- (MDRD) formula. men for at least 12 months including a ritonavir-boosted All the plasma samples were analyzed for HIV- PI plus two NRTIs and with persistently undetectable RNA level using the automated COBAS AmpliPrep plasma HIV viral load (HIV RNA < 50 copies/mL) Instrument for specimen processing and the COBAS for at least 6 months. All patients who switched to TaqMan Analyzer for amplification and detection (Roche a dual antiretroviral regimen constituted by ralte- CobasAmpliPrep/Cobas TaqMan HIV-1 tests version 2.0; gravir (400 mg twice daily) and darunavir/ritonavir Roche Diagnostics, Mannheim, Germany). Besides gag (800/100 mg daily) were enrolled in the study and fol- primers and a FAM-labeled gag probe, additional LTR lowed-up for 48 weeks. primers and a FAM-labeled LTR probe were included in Exclusion criteria were current antiretroviral regi- the assay. The two targets, gag and LTR, are amplified men including raltegravir or darunavir/ritonavir, prior with the same efficiency and the limit of quantification exposure to raltegravir or other integrase inhibitors or (LOQ), as defined by the manufacturer, was reduced to darunavir/ritonavir, previous virological failure during a 20 copies/mL. PI-based treatment, previous genotypic testing showing Viral blip was defined as an isolated plasma HIV reduced sensitivity to raltegravir or darunavir/ritonavir, RNA ≥ 20 copies/mL followed by a return to virologic HIV Clinical Trials 2016 VOL. 17 NO. 1 39 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy suppression (<20 copies/mL). Virologic failure was The adherence to the current therapy was carefully defined by a confirmed plasma HIV RNA ≥ 20 copies/mL. checked on the outpatient visits by self-reported question- The following serum markers of inflammation and naires. The study was approved by the Ethic Committee endothelial activation were evaluated: high-sensitivity of the S. Orsola-Malpighi Hospital and all participants C-reactive protein (hsCRP), interleukin-6 (IL-6), and signed an informed consent after receiving information tumor necrosis factor-α (TNF-α). HsCRP was meas- about the purpose of the study. ured by immunonephelometry on an IMMAGE analyzer (Beckman-Coulter, Villepinte, France). IL-6 and TNF-α Results were measured with a sandwich immunological assay Study inclusion criteria were met by 82 patients who were by an EVIDENCE analyzer (Medical Systems, Genova, enrolled in the study. Mean age was 45.2 years, 60 (73%) Italy). The bone health was assessed by a whole-body patients were males, mean current CD4+ lymphocyte DXA scanning (Hologic, QDR 4500A) performed at count was 679 cells/mm , mean duration of current baseline and at week 48 to evaluate total body, subtotal antiretroviral treatment was 4.6 years, and mean duration (total minus head), lumbar spine, and femoral neck bone of plasma HIV RNA < 50 copies/mL was 46.2 months. mineral density (BMD). The lipid parameters were generally abnormal (mean Darunavir/ritonavir therapy was administered by tablets total cholesterol, 258.2 mg/dL; mean triglycerides, at the standard dose of 800/100 mg once daily at break- 286.4 mg/dL). A significant percentage of patients showed fast time and after a standardized continental breakfast. abnormal proteinuria (35.4%), represented mostly by Raltegravir was swallowed by tablets at the standard dose tubular proteinuria (30.5%). Demographic, clinical, and of 400 mg twice daily at breakfast time and at supper- laboratory characteristics of study patients are summarized time. We have assessed the trough plasma concentration in Table 1. (C ) of darunavir, ritonavir, and raltegravir, which is the Current antiretroviral therapy included tenofovir/ trough standard parameter used to define the therapeutic range emtricitabine, abacavir/lamivudine or zidovudine/lami- of these drugs. The C of darunavir, ritonavir, and vudine plus lopinavir/ritonavir, and atazanavir/ritonavir trough raltegravir was assessed at steady state (>4 weeks after or fosamprenavir/ritonavir. The reasons for switch to treatment initiation), with blood samples obtained before raltegravir plus darunavir/ritonavir were renal toxicity the morning dose and 23–25 h after the previous morning (increased creatinine, hypophosphoremia, or tubular dose of darunavir/ritonavr and 11–13 h after the previous proteinuria), reduced BMD, hyperlipidemia, gastrointes- evening dose of raltegravir. The exact times of the predose tinal symptoms, or resistance to nucleoside/nucleotide sample and of the previous morning or evening intake analogues. Current antiretroviral regimens and rea- were recorded, in order to ensure accurately timed blood sons for switching treatment are presented in Table 2. sampling. C was considered to be within an accept- Particularly, all patients with increased creatinine, reduced trough able sampling timeframe if it falls within a defined time phosphoremia, or tubular proteinuria were receiving the range for darunavir every 24 h within 23–25 h after the tenofovir/emtricitabine backbone. last dose and for raltegravir every 12 h within 11–13 h In patients with resistance to NRTIs a previously per- after the last dose. formed genotypic resistance test had shown the pres- The laboratory procedures to evaluate the raltegravir, ence of ≥1 mutations in the reverse transcriptase gene darunavir, and ritonavir C are listed in the Appendix 1. associated with the resistance to ≥1 NRTIs (M184V in 6 trough Treatment failure was defined by virological failure patients, M184V + L74V in 4 patients, M184V + D67N or permanent discontinuation of either one of the two in 2 patients, and M41L + D67N in one patient). These antiretroviral drugs. Genotypic testing was performed resistance patterns did not confer a full resistance to cur- in case of virological failure. Virological success was rent NRTI backbone (tenofovir/emtricitabine in all the 13 defined as a HIV RNA < 20 copies/mL on the study patients), so all patients were virologically suppressed. dual regimen at the end of the 48-week follow-up with After 48 weeks from the switch to raltegravir plus no more than one viral blip. Results were evaluated darunavir/ritonavir, 6 discontinuations were observed: 2 both in intention-to-treat (ITT) and per-protocol (PP) discontinuations due to virological failure and 4 discontin- analyses. The ITT analysis included all subjects who uations due to non-serious adverse events. Overall, viro- switched to the dual regimen raltegravir plus darunavir/ logical success at week 48 was 92.7% in the intent-to-treat ritonavir and were enrolled into the study, while the PP analysis and 97.6% in the per-protocol analysis (Table 3). analysis included all the ITT patients except those who The first case of virological failure was observed at week discontinued the dual regimen for reasons other than 12 (HIV RNA rebound to 4,560 copies/mL) in a patient a virological failure. Missing data were considered as who had been virologically suppressed for 38 months failures. with a regimen including tenofovir/emtricitabine plus 40 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy Table 1 Baseline characteristics of the 82 patients enrolled in the study No. of patients 82 Males, No. (%) 60 (73.2) White subjects, No. (%) 78 (95.1) Age (years), mean (SD) 45.2 (18.7) HIV transmission risk category, No. (%) • IDU 16 (19.5) • MSM 36 (43.9) • Heterosexual 30 (36.6) CD4+ cell count nadir (cells/mm ), mean (SD) 219 (52) Current CD4+ lymphocyte count (cells/mm ), mean (SD) 679 (167) Duration of HIV infection (years), mean (SD) 8.3 (3.9) Duration of current ARV therapy (years), mean (SD) 4.6 (2.2) Cumulative exposure to ARV therapy (years), mean (SD) 7.9 (3.4) Duration of plasma HIV RNA < 50 copies/mL with current ARV therapy (months), mean (SD) 46.2 (18.5) Total cholesterol (mg/dL), mean (SD) 258.2 (62.4) LDL cholesterol (mg/dL), mean (SD) 147.5 (29.7) HDL cholesterol (mg/dL), mean (SD) 46.2 (15.2) Triglycerides (mg/dL), mean (SD) 286.4 (89.7) Creatinine (mg/dL), mean (SD) 1.07 (0.59) eGFR (mL/min/1.73 m ), mean (SD) 79.2 (14.6) Phosphorus (mg/dL), mean (SD) 2.61 (0.69) Patients with proteinuria >30 mg/dL, No. (%) 29 (35.4) Patients with tubular proteinuria, No. (%) 25 (30.5) BMD • Total body (g/cm ), mean (SD) 0.933 (.192) • Subtotal (g/cm ), mean (SD) 0.715 (.148) • Lumbar spine (g/cm ), mean (SD) 0.855 (.102) • Femoral neck (g/cm ), mean (SD) 0.779 (0.121) hs-CRP (mg/dL), mean (SD) 0.13 (0.11) IL-6 (pg/mL), mean (SD) 3.9 (2.5) TNF-α (pg/mL), mean (SD) 14.7 (8.5) Notes: SD, standard deviation; IDU, intravenous drug users; MSM, men who have had sex with men; ARV, antiretroviral; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate by four-variable Modification of Diet in Renal Disease (MDRD) formula ; BMD, bone mineral density; hs-CRP, high sensitivity C-reactive protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α. Table 2 Current antiretroviral treatment at the moment of the switch and reasons for switching treatment to raltegravir plus darunavir/ritonavir Current NRTIs, no (%) • Tenofovir + emtricitabine 51 (62.2) • Abacavir + lamivudine 27 (32.9) • Zidovudine + lamivudine 4 (4.9) Current PIs, No. (%) • Lopinavir/ritonavir 51 (62.2) • Atazanavir/ritonavir 20 (24.4) • Fosamprenavir/ritonavir 11 (13.4) Reasons for discontinuation • Increased creatinine, No. (%) 21 (25.6) • Hypophosphoremia, No. (%) 26 (31.7) • Tubular proteinuria, No. (%) 25 (30.5) • Reduced BMD, No. (%) 15 (18.3) • Hyperlipidemia, No. (%) 54 (65.8) • Gastrointestinal symptoms, No. (%) 41 (50) • Resistance to NRTIs, No. (%) 13 (15.8) Notes: NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; BMD, bone mineral density. atazanavir/ritonavir. The second case of virological failure adherence to cART was lower than 95% and genotypic was observed at week 24 (HIV RNA rebound to 810 cop- analysis at the time of virological failure demonstrated no ies/mL) in a patient who had been virologically suppressed resistance mutations. for 29 months with a regimen including abacavir/lamivu- The C of darunavir, ritonavir, and raltegravir was trough dine plus lopinavir/ritonavir. In both cases, the patient’s low in both patients with virological failure, confirming HIV Clinical Trials 2016 VOL. 17 NO. 1 41 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy Table 3 Immunological, virological, and biological results after the switch to raltegravir plus darunavir/ritonavir Week 24 p value Week 48 p value Treatment failures, No. (%) • Discontinuations do to AE 3 (3.7) 0.912 4 (4.9) 0.681 • Virological failures 41 (1.2) 0.774 2 (2.4) 0.439 • Loss to follow-up or missing data or 0 0 withdrew consent Virological successes, No. (%) • HIV RNA < 20 copies/mL (ITT analysis) 78 (7895.1) 0.387 76 (92.7) 0.448 • HIV RNA < 20 copies/mL (PP analysis) 81 (98.8) 0.709 80 (97.6) 0.379 Median change from baseline in CD4+ +31 (−4,+63) 0.311 +65 (+11,+101) 0.042 lymphocyte count (cells/mm ) (95% CI) Median change from baseline in serum lipids (mg/dL), (95% CI): • Total cholesterol −44.5 (−17.6,−72.5) 0.067 −37.6 (−11.5,−66.8) 0.098 • LDL cholesterol −20.6 (−5.5,−37.1) 0.089 −22.5 (−2.5,−40.1) 0.102 • HDL cholesterol +3.2 (+0.9,+5.1) 0.328 +2.8 (+0.4,+4.4) 0.562 • Triglycerides −91.4 (−42,−135) 0.012 −85.2 (−49,−126) 0.017 Median change from baseline in creatinine −0.04 (+0.02,−0.11) 0.523 −0.02 (+0.03,−0.09) 0.871 (mg/dL), (95% CI) Median change from baseline in eGFR (mL/ +2.4 (+1.1,+3.9) 0.387 +1.5 (+0.6,+3.1) 0.721 min/1.73 m ), (95% CI) Median change from baseline in phospho- +0.64 (+0.17,+0.93) 0.023 +0.58 (+0.11,+0.84) 0.031 rus (mg/dL), (95% CI) Patients with tubular proteinuria, No. (%) 19 (24.4) 11 (14.5) Change in No. of patients with tubular −6 (−24%) 0.013 −14 (−56%) 0.003 proteinuria (%) Median change from baseline in BMD (%) • Total body, mean (95% CI) −1.2 (+0.4,−1.6) 0.491 −1.3 (+0.3,−1.8) 0.792 • Lumbar spine, mean (95% CI) −1.1 (+0.5,−1.5) 0.672 −1.3 (+0.6,−1.6) 0.641 • Femoral neck, mean (95% CI) −1.3 (+0.4,−1.7) 0.581 −1.4 (+0.4,−1.6) 0.669 Median change from baseline in inflamma- tory markers • hs-CRP (mg/dL), mean (95% CI) −0.02 (−0.05,+0.01) 0.388 −0.03 (−0.06,+0.01) 0.576 • IL-6 (pg/mL), mean (95% CI) −0.97 (−1.23,−0.65) 0.021 −0.94 (−1.29,−0.58) 0.018 • TNF-α (pg/mL), mean (95% CI) −1.52 (−2.23,−0.98) 0.082 −1.33 (−2.09,−0.87) 0.792 Notes: AE, adverse event; ITT, intent-to-treat; PP, per protocol; CI, confidence interval; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate by four-variable Modification of Diet in Renal Disease (MDRD) formula ; BMD, bone mineral density; hs-CRP, high sensitivity C-reactive protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α. a poor adherence to current cART (1,205, 154, and subtotal, lumbar spine, and femoral neck) were not signif- 37 ng/ mL, respectively, in the first patient; 1,309, 172, icant. There was a significant increase in the mean serum and 42 ng/mL, respectively, in the second patient). phosphorus concentration both at week 24 (+0.64 mg/dL; The four discontinuations for non-serious adverse p = 0.023) and at week 48 (+0.58 mg/dL; p = 0.031), and events were due to diarrhea with abdominal discomfort a significant decrease in the prevalence of tubular pro- in three cases and nausea with lack of appetite in one case. teinuria both at week 24 (−24%; p = 0.013) and at week All the immunological, virological, and biological 48 (−56%; p = 0.003). results at week 24 and at week 48 after the switch are Changes in mean serum phosphorus level and preva- summarized in Table 3. lence of tubular proteinuria in patients switching from a The median increase in the CD4+ T lymphocyte count tenofovir/emtricitabine backbone are reported in Table 4. from baseline to week 48 was statistically significant With regard to the inflammation markers, a signifi- (+65 cells/mm ; p = 0.042). The change in mean serum cant reduction in the mean concentration of IL-6 both concentration of triglycerides showed a statistically signif- at week 24 (−0.97 pg/mL; p = 0.021) and at week 48 icant reduction both at week 24 (−91.4 mg/dL; p = 0.012) (−0.94 mg/ dL; p = 0.018) was reported, while changes and at week 48 (−85.2 mg/dL; p = 0.017). There was in mean levels of hs-CRP and TNF-α were not significant. also a reduction in total and LDL cholesterol levels, but No serious adverse events were reported during the it was not statistically significant, such as the increase in 48-week follow-up. No grade 3 or 4 clinical events or the HDL cholesterol level. The variations in mean values laboratory abnormalities were recorded during the study. of serum creatinine, eGFR, and BMD (both total body, The most common adverse events reported during the 42 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy Table 4 Changes in renal function parameters in the subset of 51 patients switching from tenofovir/emtricitabine plus a ritonavir boosted-protease inhibitor to raltegravir plus darunavir/ritonavir Week 24 p value Week 48 value Median change from baseline in creatinine (mg/dL), (95% CI) −0.05 (+0.03,−0.13) 0.112 −0.03 (+0.05,−0.11) 0.322 Median change from baseline in eGFR (mL/min/1.73 m ), (95% CI) +2.2 (+1.3,+3.7) 0.522 +1.7 (+0.4,+3.4) 0.401 Median change from baseline in phosphorus (mg/dL), (95% CI) +0.68 (+0.21,+0.97) 0.017 +0.64 (+0.17,+0.89) 0.009 Patients with tubular proteinuria, No. (%) 19 (37.2) 11 (21.6) Change in No. of patients with tubular proteinuria (%) −6 (−24%) 0.013 −14 (−56%) 0.003 Notes: CI, confidence interval; eGFR, estimated glomerular filtration rate by four-variable Modification of Diet in Renal Disease (MDRD) formula . median value (and range) for ritonavir C was 308 trough (154–479) ng/mL. Between and within variability of the ritonavir plasma C were 44% and 69%, respectively. trough The mean C of raltegravir was 94 ng/mL (95% CI, trough 55, 149), and the median value (and range) for raltegra- vir C was 132 (37–221) ng/mL. Between and within trough variability of the raltegravir plasma C were 82% and trough 108%, respectively (Figure 2). Between and within varia- bility of the raltegravir C were higher than those of the trough darunavir and ritonavir C , but the raltegravir concen- Figure 1 Darunavir plasma concentration. Box plot trough definition: the horizontal bar represents the mean; the box tration was above the recommended minimum effective represents the 95% confidence interval (95% CI); vertical bars concentration (15 ng/mL) in all the evaluated subjects. represent values between upper and lower limit; squares Overall, the adherence to the antiretroviral treatment represent outliers. was ≥95% in 72 out of 82 (87.8%) enrolled patients and in 70 out of 76 (92.1%) patients who completed the study. All the remaining patients had a treatment adherence ≥80%. Discussion A dual therapy based on raltegravir in combination with a ritonavir-boosted PI has been investigated mostly in antiretroviral-naïve HIV-positive subjects, while data regarding this NRTI-sparing combination as simplification strategy in antiretroviral-experienced subjects are lacking still today. In particular, raltegravir has been evaluated in Figure 2 Raltegravir plasma concentration. Box plot association with lopinavir/ritonavir, atazanavir/ritonavir, definition: the horizontal bar represents the mean; the box or darunavir/ritonavir. represents the 95% confidence interval (95% CI); vertical bars The PROGRESS study was a randomized, open- represent values between upper and lower limit; squares represent outliers. label study comparing lopinavir/ritonavir (400/100 mg twice daily) in association with tenofovir/emtricitabine (300/200 mg once daily) or raltegravir (400 mg twice follow-up were diarrhea with abdominal discomfort daily) in 206 antiretroviral-naïve HIV-1-infected patients. (5 patients; 6.1%), nausea and loss of appetite (3; 3.6%), The virological response (percentage of patients with headache (2; 2.4%), asthenia (2; 2.4%), and a slight HIV RNA < 40 copies/mL) at week 96 was comparable increase (<400 U/L) in the creatine kinase (CK) level (2; in the two treatment groups (66.3% among patients 2.4%). receiving lopinavir/ritonavir plus raltegravir and 68.6% The pharmacokinetic evaluation by the C assess- trough among those receiving lopinavir/ritonavir plus tenofovir/ ment was performed in all the 82 enrolled subjects. emtricitabine), such as the increase in the mean CD4+ The mean C of darunavir was 1,927 ng/mL (95% trough T cell count (281 cells/mm in the lopinavir/ritonavir/ CI, 1,381, 3,362), and the median value (and range) for raltegravir treatment group and 296 cells/mm in the darunavir C was 2,288 (1,205–3,744) ng/mL. Between trough lopinavir/ritonavir/tenofovir/emtricitabine group). The and within variability of the darunavir plasma C were trough safety and tolerability profiles were similar between 37% and 54%, respectively (Figure 1). The mean C trough groups, but the lopinavir/ritonavir/raltegravir regimen of ritonavir was 279 ng/mL (95% CI, 188, 445), and the HIV Clinical Trials 2016 VOL. 17 NO. 1 43 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy led to a statistically significant greater increase in the ritonavir (800/100 mg daily) plus raltegravir (400 mg peripheral fat from baseline to week 96. Moreover, twice daily) or tenofovir/emtricitabine (300/200 mg subjects treated with lopinavir/ritonavir plus raltegravir daily). After a 96-week follow-up, the NRTI-sparing showed a significantly greater increase in total bone treatment was found to be non-inferior to standard treat- mineral density and a significantly smaller decrease in ment. The Kaplan–Meier estimated proportion of treat- eGFR in comparison with patients treated with lopinavir/ ment failures and the percentage of patients with HIV ritonavir plus tenofovir/emtricitabine. RNA < 50 copies/mL were, respectively, 17.8% and The dual regimen raltegravir plus lopinavir/ritona- 89.4% in the NRTI-sparing regimen group, and 13.8% and vir was investigated also as a second-line regimen in 93.3% in the standard regimen group. The treatment fail- patients with virological failure. The SECOND-LINE ure risk was significantly higher in subjects with a baseline randomized, open-label trial enrolled 558 patients with CD4 lymphocyte count <200 cells/mm , while a post hoc confirmed plasma HIV RNA > 500 copies/mL after exploratory analysis showed a significantly greater risk ≥24 weeks of first-line treatment who were randomized of treatment failure only in those with both CD4 lym- to receive lopinavir/ritonavir plus two or three NRTIs or phocyte count <200 cells/mm and HIV RNA > 100,000 raltegravir. At 48 weeks, the proportion of subjects with copies/mL at baseline. The immunological response and HIV RNA < 200 copies/mL was comparable in the ral- the frequency of serious and non-serious adverse events tegravir group and in the NRTI group (83% and 81%, were similar in patients treated with NRTI-sparing or respectively), with a good safety profile in both groups. standard regimen, even though subjects treated with In a substudy of this trial, the raltegravir-based combina- darunavir/ritonavir plus tenofovir/emtricitabine showed a tion led to a similar improvement in limb fat but a worse significantly greater decrease in the creatinine clearance. total:HDL cholesterol ratio after 48 weeks in comparison On the contrary, this dual regimen showed a worse viro- with the NRTI-based regimen. The bone mineral density logical response in the RADAR study. In this randomized, decrease at 96 weeks was greater in patients treated with open-label trial, 85 antiretroviral-naïve adults were ran- the NRTI-based regimen than in those receiving lopinavir/ domized to receive darunavir/ritonavir (800/100 mg ritonavir plus raltegravir. once daily) in association with tenofovir/emtricitabine The effectiveness of the NRTI-sparing and ritona- (300/200 mg once daily) or raltegravir (400 mg twice vir-sparing dual regimen including atazanavir (300 mg daily). At 48 weeks, the percentage of patients with HIV twice daily) plus raltegravir (400 mg twice daily) was RNA < 48 copies/mL by the intention-to-treat analysis evaluated in the randomized, open-label SPARTAN study. was significantly lower in the raltegravir group than in the Ninety-three antiretroviral-naïve patients were rand- NRTI group (62.5% versus 83.7%, respectively), while omized to receive atazanavir plus raltegravir or atazanavir/ changes in the CD4+ T lymphocyte count, total choles- ritonavir (300/100 mg daily) plus tenofovir/emtricitabine terol/HDL cholesterol ratio, and eGFR were compara- (300/200 mg daily). After a 24-week follow-up, the pro- ble between groups. However, in patients treated with portion of patients with HIV viral load <50 copies/mL raltegravir changes in subtotal bone mineral density and was comparable in the atazanavir–raltegravir group and markers of bone metabolism were more favorable than in in the atazanavir/ritonavir/tenofovir/emtricitabine group those receiving tenofovir/emtricitabine. (74.6% and 63.3%, respectively), while both safety profile A possible lower antiviral effect of the darunavir/ and resistance risk of the experimental regimen did not ritonavir combined with raltegravir has been proposed appear satisfactory. based on a potential unfavourable pharmacokinetic The efficacy and safety of raltegravir in combina - interaction between these drugs, leading to reduced tion with darunavir/ritonavir was investigated in the darunavir plasma concentrations. However, pharma- ACTG 5262 and in the NEAT001/ANRS143 studies. cokinetic data about this potential interaction are still In the ACTG 5262 single-arm, multicenter study, 112 limited and controversial. antiretroviral-naïve patients received darunavir/ritonavir A pharmacokinetic study evaluated the plasma con- (800/100 mg daily) and raltegravir (400 mg twice daily) centrations of darunavir and ritonavir in 53 HIV-infected for 24 weeks. This dual combination was well-tolerated, adult patients with or without concomitant raltegravir but virologic failure and integrase resistance occur- administration. No significant differences were detected rence were common. Particularly, virologic failure rate about the darunavir and ritonavir C in patients receiv- trough was 16% and it was associated with baseline viral load ing or not raltegravir, but the raltegravir co-administration >100,000 copies/mL. led to a 40% reduction in the darunavir maximum con- In the NEAT001/ANRS143 European, multicenter, ran- centration (C ) and the estimate area under the curve max domized, open-label trial, 805 antiretroviral-naïve sub- 0–24 h (AUC ), as well a 60% increase in the estimated 0–24 jects were enrolled and randomized to receive darunavir/ darunavir clearance. 44 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy On the other hand, a pilot, open-label, prospective 92% of patients switching from a triple therapy including study showed a favorable pharmacokinetic profile for a ritonavir-boosted PI plus two NRTIs. This dual regimen this association. In this study, the 24-h pharmacoki- had acceptable tolerance without serious adverse events netics of darunavir and raltegravir was assessed in 15 and led to a significant improvement of some tenofovir- HIV-positive patients taking raltegravir (400 mg twice associated toxic effects, such as the reduced prevalence daily) and darunavir/ritonavir (800/100 mg once daily). of tubular proteinuria and ipophosphoremia. A significant The darunavir and raltegravir AUC , C , and C decrease in the triglyceride serum concentration was also 0–24 max trough were not significantly altered by the co-administration observed, and the patients’ adherence to the dual regimen of these drugs. Particularly, the geometric mean value was ≥95% in the 88% of cases in spite of an asymmetric of the darunavir C was 1330 ng/mL (95% CI, 1110– drug dosage (raltegravir twice daily and darunavir/ritona- trough 1760; IC for wild-type and resistant HIV-1 strains, 55 vir once daily). and 550 ng/mL, respectively) and the geometric mean The evaluation of the darunavir, ritonavir, and ralte- value of the raltegravir C was 40 ng/mL (95% CI, gravir serum concentrations showed that mean, median, trough 30–80). and range values of the C for each drug were within trough Some other NRTI-sparing associations were evaluated the therapeutic range established in previous studies and 1,23 to avoid toxic effects associated with NRTIs. In the ACTG international guidelines. Therefore, the unfavorable 5142-randomized trial, three regimens were compared for pharmacokinetic interaction between raltegravir and initial therapy: efavirenz plus two NRTIs, lopinavir/ritona- darunavir shown in other studies and leading to a signif- vir plus two NRTIs, and lopinavir-ritonavir plus efavirenz. icant decrease in the darunavir plasma exposure was not The virologic efficacy of the NRTI-sparing regimen was observed in our study. similar to that of the triple efavirenz-based combination Our work clearly presents several limitations. First, it and higher than that of the triple lopinavir–ritonavir-based was an observational study with a limited sample size regimen. However, the NRTI-sparing therapy was more and a strict selection of the study population because of likely associated with the drug resistance occurrence. numerous exclusion criteria, hence the conclusions are A dual regimen including lamivudine plus a ritona- not broadly applicable to a standard patient population. vir-boosted PI has been assessed in both antiretrovi- Second, the effectiveness of dual regimen was not com- ral-naïve and antiretroviral-experienced patients. In the pared with the standard NRTI-based triple regimen. In GARDEL-randomized trial, 426 antiretroviral-naïve spite of this, rates of virological suppression were very subjects were randomly assigned to dual therapy high and similar to those observed among subjects receiv- lopinavir/ritonavir plus lamivudine or triple therapy ing triple antiretroviral therapy in randomized clinical 28–30 lopinavir/ritonavir plus two NRTIs (in fixed-dose studies assessing other strategies of simplification. combination). After 48 weeks, virological response Another limitation was the heterogeneity of the triple was similar (also in patients with baseline viral load regimens switched to the raltegravir/darunavir/ritonavir ≥100,000 copies/mL), while toxicity-related discon- combination, that made impossible to assess the improve- tinuations were more common in the triple-therapy ment after the switch in some toxic effects associated with group. In the SALT-randomized study, 286 virologi- specific kinds of NRTIs and boosted PIs. Finally, some cally suppressed patients on stable cART were assigned aspects, such as the control of viral replication in the cen- to dual treatment atazanavir/ritonavir plus lamivu- tral nervous system or other reservoirs and the effect on dine or triple treatment atazanavir/ritonavir plus two the immune activation markers or peripheral fat were not NRTIs. After 48 weeks, dual therapy was found to be evaluated. effective, safe, and non-inferior to triple treatment. In conclusion, despite these limitations, in our study, the A retrospective study evaluated 94 virologically sup- dual therapy containing raltegravir and darunavir/ritonavir pressed treatment-experienced patients who switched was well tolerated after a 48-week follow-up as simpli- to dual regimen darunavir/ritonavir plus lamivudine fication strategy in persistently suppressed HIV-infected and showed a good profile of efficacy and safety after patients and may be particularly attractive for patients a 12-month follow-up. with genotypic resistance to NRTIs or in whom some toxic Our study is the first published work assessing the dual effects associated with the NRTI use have been reported NRTI-sparing regimen containing raltegravir (400 mg or should be avoided. Larger and properly designed ran- twice daily) and darunavir/ritonavir (800/100 mg) as sim- domized studies are certainly requested in order to better plification strategy in antiretroviral-experienced patients. evaluate the effectiveness and the safety of this strategy, This regimen after a 48-week follow-up allowed the main- as well as to better define the selected patients in whom tenance of plasma virological suppression in more than this option is applicable. HIV Clinical Trials 2016 VOL. 17 NO. 1 45 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy lopinavir/ritonavir compared with standard second-line therapy. Disclosure statement J Acquir Immune Defic Syndr. 2014;67:161–168. There are no conflicts of interest to declare. 19. Kozal MJ, Lupo S, DeJesus E, et al. A nucleoside- and ritonavir- sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naïve HIV-infected patients: SPARTAN References study results. 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Curr 2008;358:2095–2106. Opin HIV AIDS. 2011;6:285–289. 25. Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with 6. Maggi P, Bartolozzi D, Bonfanti P, et al. Renal complications in lopinavir and ritonavir plus lamivudine versus triple therapy with HIV disease: between present and future. AIDS Rev. 2012;14:37–53. lopinavir and ritonavir plus two nucleoside reverse transcriptase 7. Calza L. Renal toxicity associated with antiretroviral therapy. HIV inhibitors in antiretroviral-therapy-naïve adults with HIV-1 infection: Clin Trials. 2012;13:189–211. 48 weeks results of the randomized, open-label, non-inferiority 8. Calmy A, Fux CA, Norris R, et al. Low bone mineral density, renal GARDEL trial. Lancet Infect Dis. 2014;14:572–580. dysfunction, and fracture risk in HIV infection: a cross‐sectional 26. Perez-Molina JA, Rubio R, Rivero A, et al. Dual treatment with study. J Infect Dis. 2009;200:1746–1754. atazanavir-ritonavir plus lamivudine versus triple treatment with 9. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and atazanavir-ritonavir plus two nucleos(t)ides in virologically stable safety of once-daily darunavir/ritonavir compared with lopinavir/ patients with HIV-1 (SALT): 48 weeks results from a randomized, ritonavir in HIV-1-infected treatment naïve patients in the ARTEMIS open-label, non-inferiority trial. Lancet Infect Dis. 2015;15:775–784. trial. HIV Med. 2013;14:49–59. 27. Borghetti A, Mondi A, Piccoli B, et al. Switching to lamivudine 10. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and plus darunavir/r dual therapy in a cohort of treatment-experienced safety of raltegravir versus efavirenz when combined with tenofovir/ HIV-positive patients: the experience of an Italian centre. J Int AIDS emtricitabine in treatment-naive HIV-1-infected patients: final Soc. 2014;17:19817. 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 28. Martin A, Bloch M, Amin J, et al. 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Substitution of raltegravir compared to tenofovir/emtricitabine combined with boosted for ritonavir-boosted protease inhibitors in HIV-infected patients: the darunavir in antiretroviral-naïve patients. Impact on bone health. SPIRAL study. AIDS. 2010;24:1697–1707. PLoS One. 2014;9:e106221. 13. Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study Appendix 1 equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–254. Blood samples were collected in 3.0 mL Vacuette EDTA- 14. Dickinson L, Robinson L, Tjia J, et al. Simultaneous determination of HIV protease inhibitors amprenavir, atazanavir, indinavir, containing tubes and were centrifuged (600 g for 10 min) lopinavir, nelfinavir, ritonavir and saquinavir in human plasma to obtain plasma samples within two hours of collection. by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. The plasma samples were frozen at −20 °C and were sent 2005;829:82–90. on dry ice to the Central Laboratory of the S. Orsola- 15. Reynes J, Trinh R, Pulido F, et al. Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive Malpighi Hospital to assess the antiretroviral drugs’ C . trough subjects: 96-week results of the PROGRESS study. AIDS Res Hum After thawing, HIV was inactivated at 56 °C for 30 min, Retroviruses. 2013;29:256–265. 16. Boyd MA, Kumarasamy N, Moore CL, et al. Ritonavir-boosted then the plasma samples were extracted and subjected lopinavir plus nucleoside or nucleotide reverse transcriptase to a validated high-performance liquid chromatography inhibitors versus ritonavir-boosted lopinavir plus raltegravir for (HPLC)–tandem mass spectrometry method, as devi- treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECON-LINE): a randomized, 14 ations from the method described by Dickinson et al. open-label, non-inferiority study. Lancet. 2013;381:2091–2099. Internal standard (cimetidine) and acetonitrile (400 μL) 17. Martin A, Moore CL, Mallon PW, et al. HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2–3 were added to aliquots (100 μL) of calibrators, quality nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or controls, and patient ultrafiltrate. After mixing, cen- LPV/r + raltegravir as second-line antiretroviral therapy. PLoS One. 2013;8:e77138. trifugation, and addition of ammonium formate buffer 18. Haskelberg H, Mallon PW, Hoy J, et al. Bone mineral density over 96 (100 μL; 20 mM), samples were analyzed by HPLC–tandem weeks in adults failing first-line therapy randomized to raltegravir/ 46 HIV Clinical Trials 2016 VOL. 17 NO. 1 Calza et al. Dual Raltegravir - Darunavir/Ritonavir Dual Therapy mass spectrometry (10 μL). Fragmentation of parent the high-QC concentration (10,000 ng/mL). Inter-assay molecules into daughter ions occurred by electrospray coefficients of variation were 9.4% and 9.3% for darunavir ionization; ions were separated according to their m/z ratio and raltegravir, respectively, for the low-QC concentration, and quantified by the intensity of their respective daughter and 8% and 8.5%, respectively, for the high-QC concen- ions. The standard curves for darunavir and raltegravir tration. The corresponding accuracy ranged between 91% were linear within the ranges of 40 ng/mL to 12,000 ng/mL and 102% for darunavir, and 95–109% for raltegravir. in plasma, with a lower limit of detection of 20 ng/mL for The median C of darunavir (at 800 mg daily in asso- trough all drugs. Intra-assay coefficients of variation for darunavir ciation with ritonavir 100 mg daily) and raltegravir from and raltegravir quality control (QC) concentrations were clinical studies were 1,340 and 72 ng/mL, respectively. 9.8% and 9.1%, respectively, for the low-QC concentra- These concentrations have been used as a guideline for tion (60 ng/mL), and 8.1% and 8.9%, respectively, for analyzing the data. HIV Clinical Trials 2016 VOL. 17 NO. 1 47

Journal

HIV Clinical TrialsTaylor & Francis

Published: Jan 2, 2016

Keywords: raltegravir; darunavir; dual therapy; protease inhibitor; switch

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