Changes in Quality of Sleep, Mood, and Other Neuropsychiatric Symptoms After Switching Dolutegravir/Lamivudine/Abacavir to Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in a Randomized Study of People With Human Immunodeficiency Virus With Poor Sleep Quality: GESIDA 10418.

Background: Although switching antiretroviral therapy (ART) in people with human immunodeficiency virus experiencing insomnia due to dolutegravir-related neurotoxicity is well founded upon evidence, there is a lack of proof in regard to the outcome of stopping dolutegravir-based ART in people without insomnia but reporting poor sleep quality. Methods: This is a randomized, multicenter, open-label study to evaluate the reversibility of patient-reported sleep disturbances in patients on dolutegravir/lamivudine/abacavir without insomnia after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. The participants were randomized to switch ART at baseline or at week 4 and then completed 8 weeks of darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Our primary objective was to compare changes in sleep quality between arms at week 4. Secondary objectives were to compare changes in mood and neuropsychiatric symptoms (NS) at week 4 and 4 and 8 weeks after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. The participants completed a survey, including the Pittsburgh Sleep Quality Index (PSQI), the Hospital Anxiety and Depression scale (HADS), and specific questions to explore NS, at each visit to assess those objectives. Results: We included 72 participants. The results show that study arms were similar at baseline; however, at week 4, PSQI scores remained unchanged with dolutegravir/lamivudine/abacavir, whereas patients improved significantly after switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Similar differences between arms were also observed in HADS and NS changes. At weeks 4 and 8 after all participants switched to darunavir/cobicistat/emtricitabine/tenofovir alafenamide, we have observed significant improvements in PSQI and HAD scores and in NS. Conclusions: In patients reporting subclinical sleep disturbances without insomnia, switching from dolutegravir/lamivudine/abacavir to darunavir/cobicistat/emtricitabine/tenofovir alafenamide was associated with better sleep quality and improvements in mood and NS.

Lamivudine plus darunavir boosted with ritonavir as simplification dual regimen in HIV-infected patients.

INTRODUCTION: The combination of lamivudine plus a protease inhibitor boosted with ritonavir (PI/r) has become an alternative as simplification strategy in HIV-infected patients with toxicity/intolerance to other nucleoside analogues (NA). Lamivudine plus darunavir/r (DRV/r) could be an adequate once daily option. MATERIALS AND METHODS: Prospective cohort study of 48 HIV-infected patients on suppressive triple therapy-based HAART, HBV negative, who switched to lamivudine 300 mg plus DRV/r 800/100 mg once daily. RESULTS: Mean age was 50 yrs (35-74), and 65% were male. Thirty patients (63%) had HCV co-infection (fibrosis 4 in 7 cases, 23%). Median time of HIV infection was 19.1 years, and CD4+ count nadir was 220 cells/µL (2-604). They had received a mean of three regimens before (2-20), and 20 (42%) had a previous AIDS diagnosis. In eight cases, a previous resistance test showed two to seven secondary mutations in the protease gene, without resistance to DRV/r (one patient with the I84V mutation). At baseline, patients had viral suppression (<50 copies/mL) for a median time of 1263 days (341-1884), and they were receiving predominantly a PI based regimen (ATV in four, FPV in four, LPV in three, DRV in six) or an efavirenz-based regimen (seven). The main reason to switching to this dual therapy was toxicity (35 patients, 75%), mainly renal toxicity attributed to tenofovir (24 cases). During 104.3 patients-year of follow-up (median 912 days), only two patients (4%) failed at 27 and 505 days, due to non-adherence and lost to follow up, respectively. Total cholesterol and triglycerides increased significantly during the first six months after initiation (TC, from 185 to 269 mg/dL; p=0.01, TG from 118 to 185 mg/dL; p=0.03, TC/HDL ratio, from 4.09 to 4.66) and decreased after. Median estimated glomerular filtration rate (eGFR) improved during follow up (from 86 to 96.1 mL/min; p=0.13). In patients with renal toxicity as cause of switch there was a mild, no significant improvement during the first year (from 63.3 to 68.7 mL/min), although an improvement in protein-uria levels (protein/creatinine ratio, from 171 to 126 mg/g; p=0.04) was observed soon after initiation. CONCLUSIONS: Dual therapy with lamivudine plus darunavir boosted with ritonavir once daily is safe and effective as simplification strategy in HIV-infected patients.

A clinical and pharmacokinetic study of the combination of etravirine plus raltegravir in HIV patients with expanded intolerance or resistance.

INTRODUCTION: The combination of etravirine (ETR) plus raltegravir (RAL) could be an option for HIV patients with resistance, intolerance or important interactions with other drugs. However, there are few data on the efficacy, safety and pharmacokinetics of this dual therapy, taking into account the effect of HCV co-infection or the possible induction of ETR in the drug metabolism of RAL. MATERIAL AND METHODS: Cohort study of HIV patients initiating ETR plus RAL as dual therapy. Plasma trough levels of RAL were measured by LC/MS after at least one month on therapy. RESULTS: A total of 25 patients have been included in this combination since 2009. Mean age was 46 years, 72% were male, and 20 patients (80%) had HCV co-infection (seven patients with fibrosis 3-4). Median nadir CD4+ count was 109 (60-209), and 21 patients had an HIV RNA level below 50 copies/mL. Median time on previous therapy was 473 months (IQR, 395-570), and reasons for this dual therapy was toxicity/intolerance in 19, and interactions in nine (two chemotherapy, three DAAs, two methadone, two other). After a median follow up of 722 days (473-1088: 53.3 patients-year), there were no cases of blips or virological failure. Six patients (24%) discontinued therapy after more than 1.5 year on therapy, in four cases due to lost follow up and in two due to simplification after finishing the reason for interaction. There were no cases of liver toxicity, and only two patients increased slightly transaminases values (grade 1 and 2). Total cholesterol and triglycerides levels decrease significantly after initiation (TC, from 182 to 165 at one year; p=0.01; TG from 185 to 143 mg/dL; p=0.01). CT/HDL ratio decreases from 4.35 to 4.28 after six months. Geometric mean plasma trough level of RAL was 166 ng/mL (IQR, 40-249) and only one patient (6%) was below the in vitro IC50 of the wild type. CONCLUSIONS: The combination of ETR plus RAL as dual therapy is effective and safe in patients with expanded intolerance or interactions. There are no significant pharmacokinetic interactions between both drugs.