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Efficacy and Safety of Dolutegravir plus Boosted-Darunavir Dual Therapy among Highly Treatment-Experienced Patients

Efficacy and Safety of Dolutegravir plus Boosted-Darunavir Dual Therapy among Highly... Antiviral Therapy 2019; 24:467–471 (doi: 10.3851/IMP3319) Short communication Efc fi acy and safety of dolutegravir plus boosted‑darunavir dual therapy among highly treatment‑ experienced patients 1 1 1 1 2 1 Pilar Vizcarra , María Fontecha , Marta Monsalvo , María J Vivancos , Aurora Rojo , Jose L Casado * Department of Infectious Diseases, Ramon y Cajal Hospital, Madrid, Spain Department of Pharmacy, Ramon y Cajal Hospital, Madrid, Spain *Corresponding author e-mail: jcasado.hrc@gmail.com Background: Dual therapies decrease toxicity, pill-burden were virologically suppressed for a median of 33 months and treatment-associated cost. The combination of high (IQR 12–60). Only five patients had reduced sensitivity genetic barrier drugs such as dolutegravir plus boosted- to darunavir and mean genotypic susceptibility score of darunavir may be suitable as simplification regimen for dual therapy was 1.95 over 2. At week 48, there were patients harbouring multidrug-resistant virus. no virological failures, three patients discontinued the Methods: Patients switched to a once-daily regimen regimen due to neuropsychiatric adverse events, two consisting of dolutegravir plus darunavir, boosted with were lost to follow-up, and therefore the efficacy was cobicistat or ritonavir, were included in this cohort study. 90% (95% CI, 82, 99%, intention-to-treat analysis). The primary end point was the proportion of patients Mean estimated glomerular filtration rate decreased by with HIV RNA viral load <37 copies/ml at week  48 8.8  ml/min/1.73  m , though kidney tubular parameters, (NCT02491242). high density lipoprotein-cholesterol and triglycerides lev- Results: Overall, 51 patients were enrolled. At baseline, all els improved after switching to dual therapy. patients had failed to ≥2 antiretroviral classes. Genotypic Conclusions: In highly treatment-experienced patients resistance profiles showed a mean of primary mutations who were virologically suppressed, switching to the com- of 1.2 for non-nucleoside reverse transcriptase inhibi- bination of dolutegravir plus boosted-darunavir dual tors, 2.4 for nucleoside/nucleotide reverse transcriptase therapy was effective and well tolerated, improving lipid inhibitors and 3.5 for protease inhibitors (PIs), but they and renal parameters. Introduction Salvage regimens with the combination of multiple boosted-darunavir as switching strategies in patients antiretroviral drugs were able to fully suppress HIV with history of virological failure. replication in patients infected with multidrug-resistant virus  [1,2]. Nevertheless, high pill burden and con- Methods cerns about toxicity and costs made dual therapy strategies interesting options to maintain viral sup- We performed a Phase IV, prospective, single-arm, pression [3], especially in patients with poor compli- open-label cohort study at the HIV Unit of a ter- ance or comorbidities. Dolutegravir and darunavir are tiary university hospital from January 2015 through potent drugs with high genetic barrier and low rates of December 2017. Patients with previous virological adverse effects. The use of dolutegravir plus boosted- failures to different classes of antiretroviral drugs, but darunavir reduces pill-burden, avoiding the toxicity of virologically suppressed in a salvage regimen for at multiple-drug regimens without compromising viral least 24 weeks, were included if switched to a once- suppression. However, no or limited data are available daily regimen of dolutegravir 50 mg plus darunavir/ regarding this regimen for simplification of salvage cobicistat (DRV/c) 800 mg/150 mg, or darunavir/rito- therapies [4]. Accordingly, we assessed the efficacy and navir (DRV/r; 800 mg/100 mg). Pregnant or HBV- safety of dual regimens containing dolutegravir plus infected patients were excluded. Also, previous failure ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 467 AVT-18-SC-4422_Vizcarra.indd 467 AVT-18-SC-4422_Vizcarra.indd 467 22/11/2019 13:54:12 22/11/2019 13:54:12 P Vizcarra et al. to integrase inhibitors (InSTI) was not permitted. The follow-up, 67.58 patient-years). Baseline characteris- study was approved by our Institutional Review Board tics are shown in Table 1. Baseline HIV RNA level was (EC 280/15), and patients gave their written informed undetectable in 43 patients (83%); in 8 cases HIV RNA consent (NCT02491242). level was detectable at inclusion due to non-adherence Demographic, HIV-related and laboratory variables or recent discontinuation of the previously suppressive were recorded at baseline and every 12 weeks until antiretroviral regimen. week 48, including levels of triglycerides, total choles- Patients had received a median of 8 (IQR 4–12) terol (TC), low-density lipoprotein-cholesterol (LDL-c) regimens over 18.4 years (IQR 13.9–21.16) before and high-density lipoprotein-cholesterol (HDL-c); switching and had previous virological failure to ≥2 estimated glomerular filtration rate (eGFR) calculated antiretroviral classes at baseline. Median time of viro- with the Chronic Kidney Diseases-Epidemiological col- logical suppression with the previous regimen was 37 laboration formula [5], proteinuria expressed as urine months (IQR 18–90). The reasons for switching were protein to creatinine ratio (uPCR), tubular reabsorp- simplification, toxicity to nucleoside/nucleotide reverse tion of phosphate (TRP); nadir and baseline CD4 and transcriptase inhibitors (NRTI; renal/bone toxicity) + + + CD8 T-cell counts, CD4 /CD8 ratio, and HIV RNA and metabolic abnormalities (dyslipidaemia). Baseline level by using Versant® HIV-1 RNA 1.5 assay (kPCR; genotypic testing was available in 42 (82%) patients. Siemens Healthcare, Erlangen, Germany), threshold 37 The mean number of primary resistance mutations was copies/ml. HCV coinfection was defined as HCV anti- 3.5 for protease inhibitors (PIs; in positions I54 and bodies plus HCV-RNA-positivity. V82 predominantly), 1.2 for non-nucleoside reverse The Stanford HIVdb genotypic resistance interpreta- transcriptase inhibitors (mostly in positions Y181 and tion system was used to obtain the genotypic suscepti- K103) and 2.4 for NRTI (mainly in positions T215, bility score (GSS) of darunavir from previous genotypic M184 and M41). However, the mean GSS of dual ther- tests. The algorithm uses five categories of resistance: apy was 1.95 (range: 1–2), with only 5 patients having high-level, intermediate, low-level, potential low-level a reduced GSS to DRV. and susceptible. These categories were correlated with At week 48, there were no virological failures and a GSS of 0, 0.25, 0.50, 0.75 and 1, respectively [6]. A the efficacy was 90% (95% CI 82, 99%) in the inten- value of 1 was assigned to dolutegravir since no patient tion-to-treat analysis and 94% (95% CI 87, 100%) had virological failure while on InSTI-based therapy, as in the per-protocol analysis. Five patients had dis- defined. continued dual therapy: two because of loss to fol- The primary end point was the proportion of low-up, and three because of central nervous system patients with HIV RNA plasma viral load <37 cop- adverse events (insomnia, headache and severe anxi- ies/ml at week 48. Treatment failure was defined as ety). These patients were receiving DRV/c and were virological failure (two consecutive detectable HIV HCV-coinfected, two of them with fibrosis 4/cirrho- RNA levels), discontinuation or reintroduction of tri- sis. Median CD4 T-cell count increased from 551 3 + + ple therapy. Secondary end points included changes in to 650 cells/mm (P=0.04), median CD4 /CD8 ratio laboratory parameters. increased from 0.55 to 0.65 (+18%; P=0.80), and Mean, median and IQRs or frequencies (%) were cal- CD8 T-cell count decreased by 5% (P=0.45). There- + + culated. For GSS, the sum of the individual scores pro- fore, the variation in CD4 /CD8 ratio was primarily vided the total GSS (maximum, 2 points). Results were driven by the improvement in CD4 T-cell count. The assessed as intention-to-treat (including all patients proportion of patients with CD4 T-cell counts <200 enrolled) and per-protocol analyses (including only cell/mm decreased by 16% at week 48 (P<0.01). The those who had virological failure or discontinuation median number of pills per day decreased from 4 due to adverse events). Missing data were considered as (IQR: 1–6) to 2 (IQR: 2–3). failure. Analysis of paired observations was performed No other severe adverse events were recorded during using the Wilcoxon-rank test. Statistical significance follow-up. Mean eGFR decreased by 8.8 ml/min/1.73 m was defined at two-sided P-values <0.05. Analyses were (P<0.01). The decline in the eGFR was similar or even performed with IBM SPSS Statistics version 18 (Chi- lower in patients receiving dolutegravir plus cobi- cago, IL, USA). cistat, both inhibitors of creatinine tubular secretion, than with dolutegravir plus ritonavir (-7.6 versus -11.9 ml/min/1.73 m ; P=0.24). Globally, mean protein- Results uria improved from 91.1 to 87.2 mg/dl (P=0.86) and Overall, 51 patients switched to dolutegravir plus mean TRP from 78.8% to 80.1% (P=0.8). There was boosted-darunavir (29 patients received DRV/c, and also a non-significant increase in mean TC (1.9%), LDL-c 22 DRV/r) and they were followed-up over a median (1.4%) and HDL-c (4.3%), with reduction in mean of 29.4 months (IQR 20.6–35.1; cumulative time of TG levels (-10.3%). Noteworthy, tenofovir disoproxil 468 ©2019 International Medical Press AVT-18-SC-4422_Vizcarra.indd 468 AVT-18-SC-4422_Vizcarra.indd 468 22/11/2019 13:54:12 22/11/2019 13:54:12 Dolutegravir plus boosted-darunavir as simplification regimen Table 1. Baseline characteristics of the patients switching to Discussion dolutegravir plus boosted-darunavir Our data show the high efficacy expected with the Characteristic Value (n=51) simultaneous use of two drugs with high genetic bar- rier such as dolutegravir and boosted-darunavir as Mean age, years (range) 51.6 (33–66) Male sex, n (%) 36 (71) simplification regimen, maintaining a 90% virological Risk factors for HIV infection suppression in patients with history of multiple failures Intravenous drug use, n (%) 31 (61) harbouring multidrug-resistant strains. The simplicity Men who have sex with men, n (%) 9 (18) of this strategy could be advantageous in heavily pre- Heterosexual sex, n (%) 11 (22) treated patients without affecting efficacy, since both Median duration of HIV infection, years (IQR) 23.36 (19.2–27.0) drugs maintain viral suppression when administrated Previous AIDS diagnosis, n (%) 31 (61) once-daily as two pills [7,8]. HCV coinfection, n (%) 31 (61) Dual therapy as simplification of salvage regimens Fibrosis 4/cirrhosis, n (%) 5 (10) based on InSTI plus boosted-darunavir has been investi- + 3 Median CD4 T-cell count nadir, cells/mm (IQR) 160 (67–288) + gated mostly with raltegravir. In the SPARE study, there Median CD4 T-cell count at inclusion, 551 (243–680) was no significant difference between DRV/r plus ralte- cells/mm (IQR) + + Median CD4 /CD8 ratio (IQR) 0.55 (0.3–0.8) gravir and lopinavir/ritonavir plus tenofovir/emtricit- Median time on previous regimen, years (IQR) 3.08 (1.5–7.5) abine [9]. Several observational studies further assessed Drugs in previous regimen this combination and demonstrated viral success in DRV/r, n (%) 30 (59) 75.5% to 97.6% of patients [10–12]. The use of raltegra- DRV/r twice daily (600 mg/100 mg 16 (31) vir, a drug with relatively low genetic barrier and twice- twice daily), n (%) daily administration at that time, could have affected the Darunavir/cobicistat coformulation, n (%) 1 (2) overall results, as described in other studies [9]. Dolutegravir, n (%) 6 (12) With respect to the dual combination used in Raltegravir, n (%) 18 (35) this study, Capetti et al. [4] found that 76% reached 4-drugs, n (%) 24 (47) undetectable viral load at week 48 in a cohort of Tenofovir disoproxil fumarate, n (%) 24 (47) treatment-experienced patients switched for multiple Etravirine, n (%) 5 (10) Genotypic resistant test, n (%) 42 (82) reasons. Noteworthy, they include viral failure, 9% of Resistance to 1 ART class, n (%) 2 (4) patients had resistance mutations to InSTI, 15% had Resistance to 2 ART classes, n (%) 11 (22) reduced susceptibility to darunavir, and it was unclear Resistance to 3 ART classes, n (%) 17 (33) which patients received darunavir in a twice-daily regi- No resistance mutations, n (%) 12 (24) men. Indeed, our study provides further support about Mean GSS of dual therapy (range) 1.95 (1.5–2) the efficacy of darunavir once daily in treatment-expe- Darunavir GSS =1, n (%) 37 (73) rienced patients, even in presence of PI-resistant viruses, Darunavir GSS =0.75, n (%) 2 (4) as previously described [8,13]. Darunavir GSS =0.5, n (%) 3 (6) This dual regimen had adequate tolerance, with less Mean eGFR, ml/min/1.73 m (range) 92.6 (60.9–123.4) than 6% of patients discontinuing the drugs at week Mean uPCR (range) 91.1 (15.6–352.3) 48, due to neuropsychiatric adverse events that resolved Mean TRP, % (range) 78.8 (37.9–90.9) Mean TC, mg/dl (range) 194.96 (80–286) after changing dolutegravir. This is in line with previ- Mean LDL-c, mg/dl (range) 109.6 (28–178) ously reported rate of dolutegravir-treatment inter- Mean HDL-c, mg/dl (range) 42 (25–86) ruptions in observational studies [14]. Moreover, the Mean TG, mg/dl (range) 191 (50–815) regimen led to a non-significant improvement of pro- Cumulative time of follow-up 67.58 patient-years teinuria and tubular reabsorption of phosphate, related to tenofovir disoproxil fumarate discontinuation [15], ART, antiretroviral; DRV/r, darunavir plus ritonavir; eGFR, estimated glomerular and on the other hand, to an unexpected HDL-c and filtration rate; GSS, genotypic susceptibility score; HDL-c, high-density lipoprotein-cholesterol; LDL-c, low-density lipoprotein-cholesterol; TC, total triglyceride level improvement [16]. Interestingly, the cholesterol; TG, triglycerides; TRP, tubular reabsorption of phosphate; uPCR, decrease in eGFR in patients receiving dolutegravir and urine protein to creatinine ratio. cobicistat was similar to the use of dolutegravir indi- vidually [17], showing a lack of additive effects on the fumarate discontinuation also caused non-significant inhibition of the tubular secretion of creatinine, a fact increases in TC (4.9%; P=0.26), LDL-c (10%; P=0.25), suggesting the existence of compensatory renal mecha- HDL-c (12.4%; P=0.14) and decrease in TG (-15.1%; nisms for creatinine secretion [18]. P=0.25). Changes in laboratory parameters during fol- The limitations of this study include the observa- low-up in the overall cohort and in patients receiving tional design, decreasing the generalizability of the find- DRV/c versus DRV/r are shown in Figure 1A and 1B. ings; the absence of a triple therapy comparison group; Antiviral Therapy 24.6 469 AVT-18-SC-4422_Vizcarra.indd 469 AVT-18-SC-4422_Vizcarra.indd 469 22/11/2019 13:54:12 22/11/2019 13:54:12 P Vizcarra et al. Figure 1. Mean percentage of change in different analytical parameters during the 48 weeks of follow-up 6% 4% 2% 0% -2% -4% -6% -8% -10% eGFR uPCR TRP TC LDL-c HDL-c TG -10% -4.47% 2.43% 1.88% 1.44% 4.31% -10.33% 40% P=0.81 P=0.37 P=0.74 20% P=0.33 0% -20% P=0.24 -40% P=0.89 -60% -80% -100% P=0.89 eGFR uPCR TRP TC LDL-c HDL-c TG DRV/c -16.93% -95% 3.08% -6.22% 6.48% 4.18% -8.47% DRV/r -9.84% -76% 0.37% 8.59% 21.91% 9.64% -26.55% (A) In the overall cohort. (B) In patients receiving darunavir (DRV)/cobicistat (DRV/c) versus DRV/ritonavir (DRV/r). eGFR, estimated glomerular filtration rate; HDL-c, high-density lipoprotein-cholesterol; LDL-c, low-density lipoprotein-cholesterol; TC, total cholesterol; TG, triglycerides; TRP, tubular reabsorption of phosphate; uPCR, urine protein to creatinine ratio. 470 ©2019 International Medical Press AVT-18-SC-4422_Vizcarra.indd 470 AVT-18-SC-4422_Vizcarra.indd 470 22/11/2019 13:54:12 22/11/2019 13:54:12 Percentage of change Percentage of change Dolutegravir plus boosted-darunavir as simplification regimen 4. Capetti AF, Cossu MV, Orofino G, et al. A dual regimen a rather heterogeneous population, though representa- of ritonavir/darunavir plus dolutegravir for rescue or simplification of rescue therapy: 48 weeks’ observational tive of clinical practice; and the lack of pharmacokinetic data. BMC Infect Dis 2017; 17:658. determinations. In previous pharmacokinetic studies, 5. Levey AS, Stevens LA, Schmid CH, et al. A new equation to DRV/r co-administration resulted in non-clinically sig- estimate glomerular filtration rate. Ann Intern Med 2009; 150:604–612. nificant reductions of dolutegravir concentrations in 6. Liu TF, Shafer RW. Web resources for HIV type 1 genotypic- healthy individuals [19], while a significant increase in resistance test interpretation. Clin Infect Dis 2006; dolutegravir exposure has been reported after changing 42:1608–1618. from DRV/r to DRV/c individuals [20]. In any case, we 7. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase- did not observe higher rates of adverse events in the inhibitor-naive adults with HIV: week 48 results from the group receiving cobicistat. randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382:700–708. In conclusion, in this real-life study in treatment-expe- 8. Cahn P, Fourie J, Grinsztejn B, et al. Week 48 analysis of rienced patients, we demonstrated the maintenance of once-daily vs. twice-daily darunavir/ritonavir in treatment- viral suppression with the combination of dolutegravir experienced HIV-1-infected patients. AIDS 2011; 25:929–939. plus boosted-darunavir, even in patients with previous 9. Nishijima T, Gatanaga H, Shimbo T, et al. Switching tenofovir/emtricitabine plus lopinavir/r to raltegravir plus failure to several class of drugs and in presence of muta- darunavir/r in patients with suppressed viral load did not tions against PI, improving renal and lipid comorbidities, result in improvement of renal function but could sustain viral suppression: a randomized multicenter trial. PLoS One and reducing the number of pills. This strategy is appeal- 2013; 8:e73639. ing to reduce toxicity and pill-burden in patients har- 10. Krznaric I, Bickel M, Carganico A, et al. Similar long- bouring multidrug-resistant strains, although the relative term efficacy of dual therapy containing raltegravir and a boosted protease inhibitor versus standard triple therapies short follow-up make it mandatory to be cautious in the in pretreated HIV-1-infected patients in a retrospective, real- wide application of these results. life cohort of 14 years. HIV Med 2018; 19:662–667. 11. Calza L, Danese I, Magistrelli E, et al. Dual raltegravir- darunavir/ritonavir combination in virologically suppressed Acknowledgements HIV-1-infected patients on antiretroviral therapy including a ritonavir-boosted protease inhibitor plus two nucleoside/ nucleotide reverse transcriptase inhibitors. HIV Clin Trials We would like to thank Ana Abad (Department of 2016; 17:38–47. Infectious Diseases, Ramón y Cajal Hospital) for her 12. Madeddu G, Rusconi S, Cozzi-Lepri A, et al. Efficacy and contribution in the database management. tolerability of switching to a dual therapy with darunavir/ ritonavir plus raltegravir in HIV-infected patients with This work was supported by internal funding. HIV-1 RNA </=50 cp/ml. Infection 2017; 45:521–528. JLC, PV and MF conceived and designed the study, and 13. Boffito M, Miralles D, Hill A. Pharmacokinetics, efficacy, were responsible for patient enrolment, data analysis and safety of darunavir/ritonavir 800/100 mg once-daily in treatment-naive and -experienced patients. HIV Clin Trials and drafted and finalized the article. MM, MJV and 2008; 9:418–427. AR, were responsible for patient enrolment, clinically 14. Hoffmann C, Welz T, Sabranski M, et al. Higher rates of followed-up patients and helped to write the work. All neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med co-authors revised the manuscript, read and approved 2017; 18:56–63. the final version. 15. Casado JL, Del Rey JM, Banon S, et al. Changes in kidney All research was conducted within the guidelines of function and in the rate of tubular dysfunction after tenofovir withdrawal or continuation in HIV-infected ethical principles and local legislation. patients. J Acquir Immune Defic Syndr 2016; 72:416–422. 16. Santos JR, Saumoy M, Curran A, et al. The lipid-lowering Disclosure statement effect of tenofovir/emtricitabine: a randomized, crossover, double-blind, placebo-controlled trial. Clin Infect Dis 2015; 61:403–408. The authors declare no competing interests. 17. Yombi JC, Jones R, Pozniak A, Hougardy JM, Post FA. Monitoring of kidney function in HIV-positive patients. HIV Med 2015; 16:457–467. References 18. Lepist EI, Zhang X, Hao J, et al. Contribution of the organic 1. Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of anion transporter OAT2 to the renal active tubular secretion virologic suppression with raltegravir plus etravirine and of creatinine and mechanism for serum creatinine elevations darunavir/ritonavir among treatment-experienced patients caused by cobicistat. Kidney Int 2014; 86:350–357. infected with multidrug-resistant HIV: results of the ANRS 19. Song I, Min SS, Borland J, et al. The effect of lopinavir/ 139 TRIO trial. Clin Infect Dis 2009; 49:1441–1449. ritonavir and darunavir/ritonavir on the HIV integrase 2. Fagard C, Colin C, Charpentier C, et al. Long-term efficacy inhibitor S/GSK1349572 in healthy participants. J Clin and safety of raltegravir, etravirine, and darunavir/ritonavir Pharmacol 2011; 51:237–242. in treatment-experienced patients: week 96 results from the 20. Gervasoni C, Riva A, Cozzi V, et al. Effects of ritonavir ANRS 139 TRIO trial. J Acquir Immune Defic Syndr 2012; and cobicistat on dolutegravir exposure: when the booster 59:489–493. can make the difference. J Antimicrob Chemother 2017; 3. Boswell R, Foisy MM, Hughes CA. Dolutegravir dual 72:1842–1844. therapy as maintenance treatment in HIV-infected patients: a review. Ann Pharmacother 2018; 52:681–689. Accepted 5 June 2019; published online 7 June 2019 Antiviral Therapy 24.6 471 AVT-18-SC-4422_Vizcarra.indd 471 AVT-18-SC-4422_Vizcarra.indd 471 22/11/2019 13:54:12 22/11/2019 13:54:12 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

Efficacy and Safety of Dolutegravir plus Boosted-Darunavir Dual Therapy among Highly Treatment-Experienced Patients

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Abstract

Antiviral Therapy 2019; 24:467–471 (doi: 10.3851/IMP3319) Short communication Efc fi acy and safety of dolutegravir plus boosted‑darunavir dual therapy among highly treatment‑ experienced patients 1 1 1 1 2 1 Pilar Vizcarra , María Fontecha , Marta Monsalvo , María J Vivancos , Aurora Rojo , Jose L Casado * Department of Infectious Diseases, Ramon y Cajal Hospital, Madrid, Spain Department of Pharmacy, Ramon y Cajal Hospital, Madrid, Spain *Corresponding author e-mail: jcasado.hrc@gmail.com Background: Dual therapies decrease toxicity, pill-burden were virologically suppressed for a median of 33 months and treatment-associated cost. The combination of high (IQR 12–60). Only five patients had reduced sensitivity genetic barrier drugs such as dolutegravir plus boosted- to darunavir and mean genotypic susceptibility score of darunavir may be suitable as simplification regimen for dual therapy was 1.95 over 2. At week 48, there were patients harbouring multidrug-resistant virus. no virological failures, three patients discontinued the Methods: Patients switched to a once-daily regimen regimen due to neuropsychiatric adverse events, two consisting of dolutegravir plus darunavir, boosted with were lost to follow-up, and therefore the efficacy was cobicistat or ritonavir, were included in this cohort study. 90% (95% CI, 82, 99%, intention-to-treat analysis). The primary end point was the proportion of patients Mean estimated glomerular filtration rate decreased by with HIV RNA viral load <37 copies/ml at week  48 8.8  ml/min/1.73  m , though kidney tubular parameters, (NCT02491242). high density lipoprotein-cholesterol and triglycerides lev- Results: Overall, 51 patients were enrolled. At baseline, all els improved after switching to dual therapy. patients had failed to ≥2 antiretroviral classes. Genotypic Conclusions: In highly treatment-experienced patients resistance profiles showed a mean of primary mutations who were virologically suppressed, switching to the com- of 1.2 for non-nucleoside reverse transcriptase inhibi- bination of dolutegravir plus boosted-darunavir dual tors, 2.4 for nucleoside/nucleotide reverse transcriptase therapy was effective and well tolerated, improving lipid inhibitors and 3.5 for protease inhibitors (PIs), but they and renal parameters. Introduction Salvage regimens with the combination of multiple boosted-darunavir as switching strategies in patients antiretroviral drugs were able to fully suppress HIV with history of virological failure. replication in patients infected with multidrug-resistant virus  [1,2]. Nevertheless, high pill burden and con- Methods cerns about toxicity and costs made dual therapy strategies interesting options to maintain viral sup- We performed a Phase IV, prospective, single-arm, pression [3], especially in patients with poor compli- open-label cohort study at the HIV Unit of a ter- ance or comorbidities. Dolutegravir and darunavir are tiary university hospital from January 2015 through potent drugs with high genetic barrier and low rates of December 2017. Patients with previous virological adverse effects. The use of dolutegravir plus boosted- failures to different classes of antiretroviral drugs, but darunavir reduces pill-burden, avoiding the toxicity of virologically suppressed in a salvage regimen for at multiple-drug regimens without compromising viral least 24 weeks, were included if switched to a once- suppression. However, no or limited data are available daily regimen of dolutegravir 50 mg plus darunavir/ regarding this regimen for simplification of salvage cobicistat (DRV/c) 800 mg/150 mg, or darunavir/rito- therapies [4]. Accordingly, we assessed the efficacy and navir (DRV/r; 800 mg/100 mg). Pregnant or HBV- safety of dual regimens containing dolutegravir plus infected patients were excluded. Also, previous failure ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 467 AVT-18-SC-4422_Vizcarra.indd 467 AVT-18-SC-4422_Vizcarra.indd 467 22/11/2019 13:54:12 22/11/2019 13:54:12 P Vizcarra et al. to integrase inhibitors (InSTI) was not permitted. The follow-up, 67.58 patient-years). Baseline characteris- study was approved by our Institutional Review Board tics are shown in Table 1. Baseline HIV RNA level was (EC 280/15), and patients gave their written informed undetectable in 43 patients (83%); in 8 cases HIV RNA consent (NCT02491242). level was detectable at inclusion due to non-adherence Demographic, HIV-related and laboratory variables or recent discontinuation of the previously suppressive were recorded at baseline and every 12 weeks until antiretroviral regimen. week 48, including levels of triglycerides, total choles- Patients had received a median of 8 (IQR 4–12) terol (TC), low-density lipoprotein-cholesterol (LDL-c) regimens over 18.4 years (IQR 13.9–21.16) before and high-density lipoprotein-cholesterol (HDL-c); switching and had previous virological failure to ≥2 estimated glomerular filtration rate (eGFR) calculated antiretroviral classes at baseline. Median time of viro- with the Chronic Kidney Diseases-Epidemiological col- logical suppression with the previous regimen was 37 laboration formula [5], proteinuria expressed as urine months (IQR 18–90). The reasons for switching were protein to creatinine ratio (uPCR), tubular reabsorp- simplification, toxicity to nucleoside/nucleotide reverse tion of phosphate (TRP); nadir and baseline CD4 and transcriptase inhibitors (NRTI; renal/bone toxicity) + + + CD8 T-cell counts, CD4 /CD8 ratio, and HIV RNA and metabolic abnormalities (dyslipidaemia). Baseline level by using Versant® HIV-1 RNA 1.5 assay (kPCR; genotypic testing was available in 42 (82%) patients. Siemens Healthcare, Erlangen, Germany), threshold 37 The mean number of primary resistance mutations was copies/ml. HCV coinfection was defined as HCV anti- 3.5 for protease inhibitors (PIs; in positions I54 and bodies plus HCV-RNA-positivity. V82 predominantly), 1.2 for non-nucleoside reverse The Stanford HIVdb genotypic resistance interpreta- transcriptase inhibitors (mostly in positions Y181 and tion system was used to obtain the genotypic suscepti- K103) and 2.4 for NRTI (mainly in positions T215, bility score (GSS) of darunavir from previous genotypic M184 and M41). However, the mean GSS of dual ther- tests. The algorithm uses five categories of resistance: apy was 1.95 (range: 1–2), with only 5 patients having high-level, intermediate, low-level, potential low-level a reduced GSS to DRV. and susceptible. These categories were correlated with At week 48, there were no virological failures and a GSS of 0, 0.25, 0.50, 0.75 and 1, respectively [6]. A the efficacy was 90% (95% CI 82, 99%) in the inten- value of 1 was assigned to dolutegravir since no patient tion-to-treat analysis and 94% (95% CI 87, 100%) had virological failure while on InSTI-based therapy, as in the per-protocol analysis. Five patients had dis- defined. continued dual therapy: two because of loss to fol- The primary end point was the proportion of low-up, and three because of central nervous system patients with HIV RNA plasma viral load <37 cop- adverse events (insomnia, headache and severe anxi- ies/ml at week 48. Treatment failure was defined as ety). These patients were receiving DRV/c and were virological failure (two consecutive detectable HIV HCV-coinfected, two of them with fibrosis 4/cirrho- RNA levels), discontinuation or reintroduction of tri- sis. Median CD4 T-cell count increased from 551 3 + + ple therapy. Secondary end points included changes in to 650 cells/mm (P=0.04), median CD4 /CD8 ratio laboratory parameters. increased from 0.55 to 0.65 (+18%; P=0.80), and Mean, median and IQRs or frequencies (%) were cal- CD8 T-cell count decreased by 5% (P=0.45). There- + + culated. For GSS, the sum of the individual scores pro- fore, the variation in CD4 /CD8 ratio was primarily vided the total GSS (maximum, 2 points). Results were driven by the improvement in CD4 T-cell count. The assessed as intention-to-treat (including all patients proportion of patients with CD4 T-cell counts <200 enrolled) and per-protocol analyses (including only cell/mm decreased by 16% at week 48 (P<0.01). The those who had virological failure or discontinuation median number of pills per day decreased from 4 due to adverse events). Missing data were considered as (IQR: 1–6) to 2 (IQR: 2–3). failure. Analysis of paired observations was performed No other severe adverse events were recorded during using the Wilcoxon-rank test. Statistical significance follow-up. Mean eGFR decreased by 8.8 ml/min/1.73 m was defined at two-sided P-values <0.05. Analyses were (P<0.01). The decline in the eGFR was similar or even performed with IBM SPSS Statistics version 18 (Chi- lower in patients receiving dolutegravir plus cobi- cago, IL, USA). cistat, both inhibitors of creatinine tubular secretion, than with dolutegravir plus ritonavir (-7.6 versus -11.9 ml/min/1.73 m ; P=0.24). Globally, mean protein- Results uria improved from 91.1 to 87.2 mg/dl (P=0.86) and Overall, 51 patients switched to dolutegravir plus mean TRP from 78.8% to 80.1% (P=0.8). There was boosted-darunavir (29 patients received DRV/c, and also a non-significant increase in mean TC (1.9%), LDL-c 22 DRV/r) and they were followed-up over a median (1.4%) and HDL-c (4.3%), with reduction in mean of 29.4 months (IQR 20.6–35.1; cumulative time of TG levels (-10.3%). Noteworthy, tenofovir disoproxil 468 ©2019 International Medical Press AVT-18-SC-4422_Vizcarra.indd 468 AVT-18-SC-4422_Vizcarra.indd 468 22/11/2019 13:54:12 22/11/2019 13:54:12 Dolutegravir plus boosted-darunavir as simplification regimen Table 1. Baseline characteristics of the patients switching to Discussion dolutegravir plus boosted-darunavir Our data show the high efficacy expected with the Characteristic Value (n=51) simultaneous use of two drugs with high genetic bar- rier such as dolutegravir and boosted-darunavir as Mean age, years (range) 51.6 (33–66) Male sex, n (%) 36 (71) simplification regimen, maintaining a 90% virological Risk factors for HIV infection suppression in patients with history of multiple failures Intravenous drug use, n (%) 31 (61) harbouring multidrug-resistant strains. The simplicity Men who have sex with men, n (%) 9 (18) of this strategy could be advantageous in heavily pre- Heterosexual sex, n (%) 11 (22) treated patients without affecting efficacy, since both Median duration of HIV infection, years (IQR) 23.36 (19.2–27.0) drugs maintain viral suppression when administrated Previous AIDS diagnosis, n (%) 31 (61) once-daily as two pills [7,8]. HCV coinfection, n (%) 31 (61) Dual therapy as simplification of salvage regimens Fibrosis 4/cirrhosis, n (%) 5 (10) based on InSTI plus boosted-darunavir has been investi- + 3 Median CD4 T-cell count nadir, cells/mm (IQR) 160 (67–288) + gated mostly with raltegravir. In the SPARE study, there Median CD4 T-cell count at inclusion, 551 (243–680) was no significant difference between DRV/r plus ralte- cells/mm (IQR) + + Median CD4 /CD8 ratio (IQR) 0.55 (0.3–0.8) gravir and lopinavir/ritonavir plus tenofovir/emtricit- Median time on previous regimen, years (IQR) 3.08 (1.5–7.5) abine [9]. Several observational studies further assessed Drugs in previous regimen this combination and demonstrated viral success in DRV/r, n (%) 30 (59) 75.5% to 97.6% of patients [10–12]. The use of raltegra- DRV/r twice daily (600 mg/100 mg 16 (31) vir, a drug with relatively low genetic barrier and twice- twice daily), n (%) daily administration at that time, could have affected the Darunavir/cobicistat coformulation, n (%) 1 (2) overall results, as described in other studies [9]. Dolutegravir, n (%) 6 (12) With respect to the dual combination used in Raltegravir, n (%) 18 (35) this study, Capetti et al. [4] found that 76% reached 4-drugs, n (%) 24 (47) undetectable viral load at week 48 in a cohort of Tenofovir disoproxil fumarate, n (%) 24 (47) treatment-experienced patients switched for multiple Etravirine, n (%) 5 (10) Genotypic resistant test, n (%) 42 (82) reasons. Noteworthy, they include viral failure, 9% of Resistance to 1 ART class, n (%) 2 (4) patients had resistance mutations to InSTI, 15% had Resistance to 2 ART classes, n (%) 11 (22) reduced susceptibility to darunavir, and it was unclear Resistance to 3 ART classes, n (%) 17 (33) which patients received darunavir in a twice-daily regi- No resistance mutations, n (%) 12 (24) men. Indeed, our study provides further support about Mean GSS of dual therapy (range) 1.95 (1.5–2) the efficacy of darunavir once daily in treatment-expe- Darunavir GSS =1, n (%) 37 (73) rienced patients, even in presence of PI-resistant viruses, Darunavir GSS =0.75, n (%) 2 (4) as previously described [8,13]. Darunavir GSS =0.5, n (%) 3 (6) This dual regimen had adequate tolerance, with less Mean eGFR, ml/min/1.73 m (range) 92.6 (60.9–123.4) than 6% of patients discontinuing the drugs at week Mean uPCR (range) 91.1 (15.6–352.3) 48, due to neuropsychiatric adverse events that resolved Mean TRP, % (range) 78.8 (37.9–90.9) Mean TC, mg/dl (range) 194.96 (80–286) after changing dolutegravir. This is in line with previ- Mean LDL-c, mg/dl (range) 109.6 (28–178) ously reported rate of dolutegravir-treatment inter- Mean HDL-c, mg/dl (range) 42 (25–86) ruptions in observational studies [14]. Moreover, the Mean TG, mg/dl (range) 191 (50–815) regimen led to a non-significant improvement of pro- Cumulative time of follow-up 67.58 patient-years teinuria and tubular reabsorption of phosphate, related to tenofovir disoproxil fumarate discontinuation [15], ART, antiretroviral; DRV/r, darunavir plus ritonavir; eGFR, estimated glomerular and on the other hand, to an unexpected HDL-c and filtration rate; GSS, genotypic susceptibility score; HDL-c, high-density lipoprotein-cholesterol; LDL-c, low-density lipoprotein-cholesterol; TC, total triglyceride level improvement [16]. Interestingly, the cholesterol; TG, triglycerides; TRP, tubular reabsorption of phosphate; uPCR, decrease in eGFR in patients receiving dolutegravir and urine protein to creatinine ratio. cobicistat was similar to the use of dolutegravir indi- vidually [17], showing a lack of additive effects on the fumarate discontinuation also caused non-significant inhibition of the tubular secretion of creatinine, a fact increases in TC (4.9%; P=0.26), LDL-c (10%; P=0.25), suggesting the existence of compensatory renal mecha- HDL-c (12.4%; P=0.14) and decrease in TG (-15.1%; nisms for creatinine secretion [18]. P=0.25). Changes in laboratory parameters during fol- The limitations of this study include the observa- low-up in the overall cohort and in patients receiving tional design, decreasing the generalizability of the find- DRV/c versus DRV/r are shown in Figure 1A and 1B. ings; the absence of a triple therapy comparison group; Antiviral Therapy 24.6 469 AVT-18-SC-4422_Vizcarra.indd 469 AVT-18-SC-4422_Vizcarra.indd 469 22/11/2019 13:54:12 22/11/2019 13:54:12 P Vizcarra et al. Figure 1. Mean percentage of change in different analytical parameters during the 48 weeks of follow-up 6% 4% 2% 0% -2% -4% -6% -8% -10% eGFR uPCR TRP TC LDL-c HDL-c TG -10% -4.47% 2.43% 1.88% 1.44% 4.31% -10.33% 40% P=0.81 P=0.37 P=0.74 20% P=0.33 0% -20% P=0.24 -40% P=0.89 -60% -80% -100% P=0.89 eGFR uPCR TRP TC LDL-c HDL-c TG DRV/c -16.93% -95% 3.08% -6.22% 6.48% 4.18% -8.47% DRV/r -9.84% -76% 0.37% 8.59% 21.91% 9.64% -26.55% (A) In the overall cohort. (B) In patients receiving darunavir (DRV)/cobicistat (DRV/c) versus DRV/ritonavir (DRV/r). eGFR, estimated glomerular filtration rate; HDL-c, high-density lipoprotein-cholesterol; LDL-c, low-density lipoprotein-cholesterol; TC, total cholesterol; TG, triglycerides; TRP, tubular reabsorption of phosphate; uPCR, urine protein to creatinine ratio. 470 ©2019 International Medical Press AVT-18-SC-4422_Vizcarra.indd 470 AVT-18-SC-4422_Vizcarra.indd 470 22/11/2019 13:54:12 22/11/2019 13:54:12 Percentage of change Percentage of change Dolutegravir plus boosted-darunavir as simplification regimen 4. Capetti AF, Cossu MV, Orofino G, et al. A dual regimen a rather heterogeneous population, though representa- of ritonavir/darunavir plus dolutegravir for rescue or simplification of rescue therapy: 48 weeks’ observational tive of clinical practice; and the lack of pharmacokinetic data. BMC Infect Dis 2017; 17:658. determinations. In previous pharmacokinetic studies, 5. Levey AS, Stevens LA, Schmid CH, et al. A new equation to DRV/r co-administration resulted in non-clinically sig- estimate glomerular filtration rate. Ann Intern Med 2009; 150:604–612. nificant reductions of dolutegravir concentrations in 6. Liu TF, Shafer RW. Web resources for HIV type 1 genotypic- healthy individuals [19], while a significant increase in resistance test interpretation. Clin Infect Dis 2006; dolutegravir exposure has been reported after changing 42:1608–1618. from DRV/r to DRV/c individuals [20]. In any case, we 7. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase- did not observe higher rates of adverse events in the inhibitor-naive adults with HIV: week 48 results from the group receiving cobicistat. randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382:700–708. In conclusion, in this real-life study in treatment-expe- 8. Cahn P, Fourie J, Grinsztejn B, et al. 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Similar long- bouring multidrug-resistant strains, although the relative term efficacy of dual therapy containing raltegravir and a boosted protease inhibitor versus standard triple therapies short follow-up make it mandatory to be cautious in the in pretreated HIV-1-infected patients in a retrospective, real- wide application of these results. life cohort of 14 years. HIV Med 2018; 19:662–667. 11. Calza L, Danese I, Magistrelli E, et al. Dual raltegravir- darunavir/ritonavir combination in virologically suppressed Acknowledgements HIV-1-infected patients on antiretroviral therapy including a ritonavir-boosted protease inhibitor plus two nucleoside/ nucleotide reverse transcriptase inhibitors. HIV Clin Trials We would like to thank Ana Abad (Department of 2016; 17:38–47. Infectious Diseases, Ramón y Cajal Hospital) for her 12. Madeddu G, Rusconi S, Cozzi-Lepri A, et al. Efficacy and contribution in the database management. tolerability of switching to a dual therapy with darunavir/ ritonavir plus raltegravir in HIV-infected patients with This work was supported by internal funding. HIV-1 RNA </=50 cp/ml. Infection 2017; 45:521–528. JLC, PV and MF conceived and designed the study, and 13. Boffito M, Miralles D, Hill A. Pharmacokinetics, efficacy, were responsible for patient enrolment, data analysis and safety of darunavir/ritonavir 800/100 mg once-daily in treatment-naive and -experienced patients. HIV Clin Trials and drafted and finalized the article. MM, MJV and 2008; 9:418–427. AR, were responsible for patient enrolment, clinically 14. Hoffmann C, Welz T, Sabranski M, et al. Higher rates of followed-up patients and helped to write the work. All neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med co-authors revised the manuscript, read and approved 2017; 18:56–63. the final version. 15. Casado JL, Del Rey JM, Banon S, et al. Changes in kidney All research was conducted within the guidelines of function and in the rate of tubular dysfunction after tenofovir withdrawal or continuation in HIV-infected ethical principles and local legislation. patients. J Acquir Immune Defic Syndr 2016; 72:416–422. 16. Santos JR, Saumoy M, Curran A, et al. The lipid-lowering Disclosure statement effect of tenofovir/emtricitabine: a randomized, crossover, double-blind, placebo-controlled trial. Clin Infect Dis 2015; 61:403–408. The authors declare no competing interests. 17. Yombi JC, Jones R, Pozniak A, Hougardy JM, Post FA. Monitoring of kidney function in HIV-positive patients. HIV Med 2015; 16:457–467. References 18. Lepist EI, Zhang X, Hao J, et al. Contribution of the organic 1. Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of anion transporter OAT2 to the renal active tubular secretion virologic suppression with raltegravir plus etravirine and of creatinine and mechanism for serum creatinine elevations darunavir/ritonavir among treatment-experienced patients caused by cobicistat. Kidney Int 2014; 86:350–357. infected with multidrug-resistant HIV: results of the ANRS 19. Song I, Min SS, Borland J, et al. The effect of lopinavir/ 139 TRIO trial. Clin Infect Dis 2009; 49:1441–1449. ritonavir and darunavir/ritonavir on the HIV integrase 2. Fagard C, Colin C, Charpentier C, et al. Long-term efficacy inhibitor S/GSK1349572 in healthy participants. J Clin and safety of raltegravir, etravirine, and darunavir/ritonavir Pharmacol 2011; 51:237–242. in treatment-experienced patients: week 96 results from the 20. Gervasoni C, Riva A, Cozzi V, et al. Effects of ritonavir ANRS 139 TRIO trial. J Acquir Immune Defic Syndr 2012; and cobicistat on dolutegravir exposure: when the booster 59:489–493. can make the difference. J Antimicrob Chemother 2017; 3. Boswell R, Foisy MM, Hughes CA. Dolutegravir dual 72:1842–1844. therapy as maintenance treatment in HIV-infected patients: a review. Ann Pharmacother 2018; 52:681–689. Accepted 5 June 2019; published online 7 June 2019 Antiviral Therapy 24.6 471 AVT-18-SC-4422_Vizcarra.indd 471 AVT-18-SC-4422_Vizcarra.indd 471 22/11/2019 13:54:12 22/11/2019 13:54:12

Journal

Antiviral Therapy – SAGE

Published: Aug 1, 2019

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