Effectiveness of Once/Day Dolutegravir Plus Boosted Darunavir as a Switch Strategy in Heavily Treated Patients with Human Immunodeficiency Virus

Abstract

STUDY OBJECTIVE Dual therapy with once/day dolutegravir (DTG) plus boosted darunavir (DRV/b) may be a suitable and effective strategy with a high genetic barrier to resistance in patients infected with human immunodeficiency virus (HIV). Our aim was to evaluate the effectiveness of DTG plus DRV/b (DTG+DRV/b) as a switch strategy in HIV-infected patients, irrespective of their history of virologic failure (VF). DESIGN Multicenter retrospective cohort study. SETTING Human immunodeficiency outpatient treatment clinics at three university hospitals in Spain. PATIENTS Fifty HIV-infected adults who had a stable antiretroviral treatment (ART) regimen and an undetectable viral load for at least 6 months, and whose ART was switched to once/day DTG+DRV/b between January 2015 and January 2018 were included in the analysis. Historical genotype at the time of VF was available in 44 patients. MEASUREMENTS AND MAIN RESULTS Patients were followed until VF or treatment discontinuation for any reason. The primary outcome was the percentage of patients with a viral load of 50 copies/mL or lower at the last follow-up visit. Secondary outcomes included changes in CD4 + cell count, lipid profile, and renal function. Of the 50 patients included, median time of viral suppression was 52 months (interquartile range [IQR] 18-103 mo) and nadir CD4 + 89 cells/mm 3 (IQR 37-241 cells/ mm 3 ). Patients had a history of a median of 8 ART combinations (IQR 4-11 combinations) and 3 VFs (IQR 2-8 VFs). The historical genotypes from 44 patients showed 41 patients (93.2%) with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs), 32 (72.7%) with nonnucleoside reverse transcriptase inhibitor (NNRTI) RAMs, and 12 (27.3%) with primary protease inhibitor (PI) RAMs; 7 (15.9%) had darunavir RAMs, and no patients had baseline integrase strand transfer inhibitor RAMs. Thirty-seven patients (84.1%) had resistance to at least two antiretroviral classes. After a median of 25 months (IQR 17-28 mo) of follow-up, 49 patients (98%) maintained a viral load of 50 copies/mL or lower, and 1 patient (2%) had VF. No new RAMs emerged at VF. At week 4, serum creatinine concentration increased a median of 0.12 mg/dl (0.03-0.23 mg/dl). At last visit, total cholesterol and low-density lipoprotein cholesterol levels increased by a median of 9 mg/dl (IQR À18 to 40 mg/dl) and 16 mg/dl (IQR À9 to 40 mg/dl), respectively, whereas CD4 + cell count remained stable (median +13 cell/mm 3 ). CONCLUSION In this cohort of heavily treated HIV-infected patients with virologic suppression, switching to the combination of DTG+DRV/b was a convenient regimen that was highly effective and had good tolerability. B R I E F R E P O R T S

Clinical outcomes of once-daily darunavir in treatment-experienced patients with darunavir resistance-associated mutations through 48 weeks of treatment

“…Interestingly, 9/15 patients received DRV in combination with DTG; five on DRV/r plus DTG and four on DRV/c plus DTG, all nine patients were suppressed at week 48. Previous data have demonstrated good efficacy and safety of DTG plus boosted-DRV dual therapy among highly treatment-experienced patients with ARV resistance 13,14 and have found that switching from DRV/r to DRV/c results in significantly increased DTG trough concentrations. 20 This effect is presumed to be due to decreases in DTG concentrations mediated by ritonavir's induction of DTG metabolism via glucuronidation.…”

“…12 Real-world data from small cohorts of highly treatment-experienced patients switched to once-daily regimens of boosted DRV in combination with dolutegravir (DTG) demonstrated virologic suppression in 98-100% of patients through a median follow-up period of 12-25 months. 13,14 A minority of patients in these studies had DRV RAMs (n ¼ 12) but still achieved virologic efficacy with this treatment strategy. 13,14 One case report describes successful use of once-daily high-dose DRV and DTG in a patient with multi-drug resistant (MDR) HIV harboring three DRV RAMs to achieve virologic suppression through 18 months; however, TDM was used to guide and select a higher than standard once-daily DRV boosted with ritonavir (DRV/r) dosage (1200/100 mg) in this case.…”

“…13,14 A minority of patients in these studies had DRV RAMs (n ¼ 12) but still achieved virologic efficacy with this treatment strategy. 13,14 One case report describes successful use of once-daily high-dose DRV and DTG in a patient with multi-drug resistant (MDR) HIV harboring three DRV RAMs to achieve virologic suppression through 18 months; however, TDM was used to guide and select a higher than standard once-daily DRV boosted with ritonavir (DRV/r) dosage (1200/100 mg) in this case. 15 Based on these findings, further data would be useful to support the use of once-daily DRV in patients with !1 DRV RAMs.…”

Dolutegravir with boosted darunavir as treatment simplification for treatment-experienced HIV patients with multiple mutations

“…Results from relevant studies are similar to our findings concluding that DTGþDRV/c is highly effective and well tolerated. [3][4][5][6][7] Although these studies are few, having small study populations and short follow-up, this dual therapy regimen seems very promising in HIV resistance. It has the advantage of a high genetic barrier, it is NRTI-sparing and has oncedaily administration.…”

“…DTG+DRV/c is attractive as a salvage regimen for this population due to the absence of reverse transcriptase analogues, high genetic barrier and simplicity. 2,3…”