Dolutegravir plus rilpivirine as dual regimen in virologically suppressed HIV-1 infected patients in a clinical setting.

Objectives: There are scarce data on the combination of dolutegravir (DTG) plus rilpivirine (RPV) in the real world, including patients with hepatitis C virus (HCV) coinfection, toxicity or previous failure, or at risk for severe drug-drug interactions (DDIs). Methods: Prospective cohort study of virologically suppressed HIV-1 infected patients, without resistance to DTG or RPV, switched to this dual regimen because of toxicity or risk of DDIs (NCT02491242). Results: Overall, 102 patients (mean age 54 years, 28% women) were included. Fifty-seven were coinfected with HCV (fibrosis grade 4 in 27 cases, 1 liver transplantation). Seven patients had chronic kidney disease (1 renal transplantation). At week 48, only 1 virologic failure occurred (<1%), and 6 patients (6%) left the regimen (3 with central nervous system adverse events, 1 each due to pregnancy, metformin interaction, and lost to follow up). Thus, the overall treatment success rates were 93% (95% CI, 88%-98%; ITT-e, snapshot analysis) and 96% (95% CI, 92%-99%; per protocol analysis). The CD4/CD8 ratio increased slightly (median, +0.03). Triglycerides levels improved significantly (-18.8%, p < 0.01). The creatinine-based estimated glomerular filtration rate decreased by a mean of -8.4 ml/min/1.73 m2, but tubular renal parameters improved. A paired dual X-ray absorptiometry scan showed a mild improvement in spine (mean, +1.15%; -0.57 to +3.3%) and in femoral neck bone mineral density (mean, +0.4%; -3.3% to +2.57%). Conclusions: In the clinical setting, switching to the combination of DTG plus rilpivirine in virologically suppressed HIV-1 patients is effective and safe, and improves lipid, renal and bone evolution.

Efficacy and safety of dolutegravir plus boosted-darunavir dual therapy among highly treatment-experienced patients.

BACKGROUND: Dual therapies decrease toxicity, pill-burden and treatment-associated cost. The combination of high genetic barrier drugs such as dolutegravir plus boosted-darunavir may be suitable as simplification regimen for patients harbouring multidrug-resistant virus. METHODS: Patients switched to a once-daily regimen consisting of dolutegravir plus darunavir, boosted with cobicistat or ritonavir, were included in this cohort study. The primary end point was the proportion of patients with HIV RNA viral load <37 copies/ml at week 48 (NCT02491242). RESULTS: Overall, 51 patients were enrolled. At baseline, all patients had failed to ≥2 antiretroviral classes. Genotypic resistance profiles showed a mean of primary mutations of 1.2 for non-nucleoside reverse transcriptase inhibitors, 2.4 for nucleoside/nucleotide reverse transcriptase inhibitors and 3.5 for protease inhibitors (PIs), but they were virologically suppressed for a median of 33 months (IQR 12-60). Only five patients had reduced sensitivity to darunavir and mean genotypic susceptibility score of dual therapy was 1.95 over 2. At week 48, there were no virological failures, three patients discontinued the regimen due to neuropsychiatric adverse events, two were lost to follow-up, and therefore the efficacy was 90% (95% CI, 82, 99%, intention-to-treat analysis). Mean estimated glomerular filtration rate decreased by 8.8 ml/min/1.73 m2, though kidney tubular parameters, high density lipoprotein-cholesterol and triglycerides levels improved after switching to dual therapy. CONCLUSIONS: In highly treatment-experienced patients who were virologically suppressed, switching to the combination of dolutegravir plus boosted-darunavir dual therapy was effective and well tolerated, improving lipid and renal parameters.

CD4/CD8 ratio improvement in HIV-1-infected patients receiving dual antiretroviral treatment.

The CD4/CD8 ratio is an indirect marker of immune activation, immune senescence, and inflammation in HIV infection. We performed a prospective study of the CD4/CD8 ratio evolution in 245 virally-suppressed (median, 55 months) HIV-infected patients (29% females) who had switched to four dual antiretroviral regimens. At baseline, the median CD4/CD8 ratio was 0.71 (interquartile range, IQR, 0.46-0.97), associated with duration of HIV infection, nadir CD4+ cell count, and AIDS diagnosis. It was lower in the case of hepatitis C virus coinfection and cardiovascular disease (p = 0.09), but the ratio was higher in patients with chronic kidney disease, proteinuria, or osteoporosis. At 48 weeks, the median CD4/CD8 ratio increased by 3% (+0.02; IQR, -0.07, +0.09; p = 0.07); greater improvement was observed in patients with lower baseline ratios and previous AIDS diagnosis. The slope of increase was slower in patients with the highest baseline values. Also, there were no differences in the CD4/CD8 ratio increase according to type of dual regimen, after adjusting for baseline and HIV-related values. In conclusion, CD4/CD8 ratio increase is observed during suppressive dual regimens, and its extent is related to baseline values and previous HIV-related factors. Longer duration on antiretroviral therapy and drug toxicity could affect the evolution of this marker in the presence of comorbidities.

Long-term improvement in renal, bone, lipid parameters, and CD4/CD8 ratio in HIV-infected patients switching to a dual therapy with lamivudine plus boosted darunavir.

BACKGROUND: Dual therapies have been tested in selected patients, but there is no evidence for its advantages in clinical practice. The aim of this study was to evaluate in the clinical setting the long-term outcomes and the impacts on comorbidities of a dual therapy based on lamivudine plus darunavir boosted with ritonavir (DRV/r). METHODS: A prospective cohort study of 106 patients who were switched to this dual regimen from April 2014 to December 2017 because of renal and bone toxicity, intolerance, or physician's decision was conducted. The primary study endpoint was the proportion of patients who were free of treatment failure at 48 and 96 weeks. RESULTS: The mean age was 50 years, and 64% were hepatitis C virus-coinfected. At 48 weeks, the efficacy was 95% (95% confidence interval, 91-99%; ITT-e analysis; two changes due to toxicity, three because of drug-drug interactions -DDIs-). At week 96, 26 patients (25%) had discontinued this therapy (two virologic failures, one additional adverse event, 18 therapy changes to avoid DDIs). An increase in lipid parameters was observed during the first 6-12 months in the group discontinuing tenofovir disoproxil fumarate (p < .01), which was partly corrected at 96 weeks. Improvements in CD4/CD8 ratio (p = .04), bone mineral density (+1.17%; p = .07), estimated glomerular filtration rate (+7.7 mL/min in CKD patients; p = .02), urinary parameters (proteinuria, -23%), and overall cost (-43%) were observed. CONCLUSIONS: Our results demonstrated the long-term efficacy and safety of an antiretroviral regimen based on dual therapy with lamivudine plus boosted darunavir in the clinical setting.

Symtuza® in clinical practice. / Symtuza® (DRV/c/FTC/TAF) en la práctica clínica.

Because lifelong therapy is needed in HIV infection, high long-term adherence is necessary. Darunavir/co-bicistat/emtricitabina/tenofovir alafenamide (Symtuza®) is the first triple therapy combining a protease inhibitor (PI) in a single tablet regimen. This drug combines the potency and high genetic barrier of the most effective PI, darunavir, with the renal and bone safety of tenofovir alafenamide. Phase 3 studies have demonstrated its non-inferiority in achieving virologic suppression and maintaining efficacy in virological-ly suppressed patients, even in those with previous failure. Although long-term data are needed, Symtuza® has become a preferred option in most patients. The drug is especially useful in patients with suspected poor adherence, those requiring rapid treatment initiation because of late presentation or opportunistic infection, patients with limitations for other alternatives, and those with a history of previous failure or resistance to other classes of drugs. Supplement information: This article is part of a supplement entitled "Co-formulated cobicistat-boosted darunavir, emtricitabine, and tenofovir alafenamide for the treatment of HIV infection", which is sponsored by Janssen.

Symtuza(R) (DRV/c/FTC/TAF) en la práctica clínica / Symtuza(R)in clinical practice

La infección por el VIH exige una alta adherencia al tratamiento a largo plazo al tratarse este de un tratamiento de por vida. Darunavir/cobicistat/emtricitabina/tenofovir alafenamida (Symtuza(R)) es la primera tri-terapia con un inhibidor de la proteasa (IP) en un comprimido. Combina la potencia y una alta barrera genética del mejor IP, darunavir, con la seguridad renal y ósea de tenofovir alafenamida. Estudios en fase III han demostrado que esta coformulación no es inferior en alcanzar la supresión virológica y en el mantenimiento de la eficacia en pacientes inmunosuprimidos, incluso con antecedentes de fracaso previo. Aunque son precisos datos a largo plazo, Symtuza(R) se convierte en una opción preferente de uso en la mayoría de los pacientes y, en especial, en pacientes en quienes se sospecha baja adherencia, que necesitan un inicio rápido del tratamiento antirretroviral por presentación tardía o infección oportunista, que tienen limitaciones respecto a otras coformulaciones y en aquellos con antecedentes de fracaso previo o resistencias a otras familias. Información sobre el suplemento: este artículo forma parte del suplemento titulado "Darunavir, cobicistat, emtricitabina y tenofovir alafenamida coformulados en el tratamiento de la infección por el VIH", que ha sido patrocinado por Janssen

Because lifelong therapy is needed in HIV infection, high long-term adherence is necessary. Darunavir/co-bicistat/emtricitabina/tenofovir alafenamide (Symtuza(R)) is the first triple therapy combining a protease inhibitor (PI) in a single tablet regimen. This drug combines the potency and high genetic barrier of the most effective PI, darunavir, with the renal and bone safety of tenofovir alafenamide. Phase 3 studies have demonstrated its non-inferiority in achieving virologic suppression and maintaining efficacy in virological-ly suppressed patients, even in those with previous failure. Although long-term data are needed, Symtuza(R) has become a preferred option in most patients. The drug is especially useful in patients with suspected poor adherence, those requiring rapid treatment initiation because of late presentation or opportunistic infection, patients with limitations for other alternatives, and those with a history of previous failure or resistance to other classes of drugs. Supplement information: This article is part of a supplement entitled "Co-formulated cobicistat-boosted darunavir, emtricitabine, and tenofovir alafenamide for the treatment of HIV infection", which is sponsored by Janssen

Dolutegravir and rilpivirine for the maintenance treatment of virologically suppressed HIV-1 infection.

INTRODUCTION: Triple combinations of antiretroviral therapy (ART) drugs are the standard treatment for human immunodeficiency virus (HIV) infection, but the challenges include long-term side effects, high costs, and adherence. The recent advent of potent and well-tolerated ART has renewed the interest for newer ART strategies. A dual regimen with the combination of dolutegravir (DTG) and rilpivirine (RPV), two well-tolerated, metabolic-friendly, and potent drugs could offer additional benefits. Areas covered: A review of recent randomized trials and observational cohorts concerning the use of a dual therapy with DTG plus RPV as a switching strategy in patients with viral suppression. Expert commentary: Currently, data of more of 900 patients switched to this dual regimen are available. This combination shows a high rate of virological suppression, above 90% at 48 weeks, few discontinuations due to adverse events, improvement in bone and kidney parameters for patients discontinuing tenofovir disoproxil fumarate, lack of loss of the inflammatory control achieved with triple therapy, and a neutral effect on lipid parameters. Thus, for the first time, a dual regimen without protease inhibitors is effective, avoiding metabolic side effects and drug interactions. Longer follow-up is needed, but this dual regimen appears as a promising strategy for aging HIV-infected patients.