Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority Trial.

BACKGROUND: Doravirine (DOR) is a nonnucleoside reverse-transcriptase inhibitor. In the phase 3 DRIVE-AHEAD trial in treatment-naive adults with human immunodeficiency virus type 1 (HIV-1) infection, DOR demonstrated noninferior efficacy compared with efavirenz (EFV) and superior profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96. METHODS: DRIVE-AHEAD is a phase 3, multicenter, double-blind, noninferiority trial in antiretroviral treatment-naive adults with HIV-1 RNA ≥1000 copies/mL. Participants were randomized to a daily fixed-dose tablet of DOR (100 mg), lamivudine (3TC; 300 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) (DOR/3TC/TDF) or EFV (600 mg), emtricitabine (FTC; 200 mg) and TDF (300 mg) (EFV/FTC/TDF). The efficacy end point of interest at week 96 was the proportion of participants with HIV-1 RNA levels <50 copies/mL (Food and Drug Administration Snapshot Approach) with a predefined noninferiority margin of 10% to support week 48 results. Safety end points of interest included prespecified neuropsychiatric adverse events and the mean change in fasting lipids at week 96. RESULTS: Of 734 participants randomized, 728 received study drugs and were included in analyses. At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF vs 73.6% of EFV/FTC/TDF participants, with a treatment difference of 3.8% (95% confidence interval, -2.4% to 10%). Virologic failure rates were low and similar across treatment arms, with no additional resistance to DOR observed between weeks 48 and 96. Prespecified neuropsychiatric adverse events and rash were less frequent in DOR/3TC/TDF than in EFV/FTC/TDF participants through week 96. At week 96, fasting low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol (HDL-C) levels increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group; the mean changes from baseline in total cholesterol/HDL-C ratio were similar. CLINICAL TRIALS REGISTRATION: NCT02403674.

A Health Literate Patient-focused Approach to the Redesign of the Raltegravir (ISENTRESS) Pediatric Kit and Instructions for Use.

BACKGROUND: Limited data exist regarding how medications for pediatric use can be developed to minimize medication errors. The integrase inhibitor raltegravir was developed for use in neonates (≥2 kg). Anticipating that neonatal administration would be performed primarily by mothers with varying degrees of health literacy, a health literate, patient-focused, iterative process was conducted to update/redesign the raltegravir granules for oral suspension pediatric kit and instructions for use (IFU) for neonatal use to be ready for regulatory submission. METHODS: Prototypes of an updated/redesigned raltegravir IFU were systematically assessed through multi-stage, iterative testing and evaluation involving untrained lay individuals with varying levels of health literacy, healthcare professionals and health literacy experts. RESULTS: This iterative process resulted in numerous refinements to the IFU and kit, including wording, layout, presentation, colored syringes and additional instructional steps. The revised raltegravir pediatric kit and IFU (to include neonatal dosing) were approved by the US Food and Drug Administration in 2017 and the European Union in 2018. No reported medication errors related to IFU utilization had been reported as of March 2021, reflecting >3 years of commercial use worldwide. CONCLUSIONS: This patient-focused process produced health literate instructions for preparing and administering an antiretroviral for neonatal use with complex dosing requirements. Testing demonstrated that lay users with a range of health literacy levels were able to accurately mix, measure and administer the product. This process demonstrates how a neonatal medication can be optimized for use through collaboration between the infectious disease expert community and a manufacturer.

Efficacy, safety and central nervous system effects after switch from efavirenz/tenofovir/emtricitabine to doravirine/tenofovir/lamivudine.

OBJECTIVE: Doravirine is an alternative treatment option for individuals who do not tolerate efavirenz. We assessed efficacy, safety, and CNS effects in adults with HIV-1 and CNS complaints who switched from an efavirenz-based regimen to a doravirine-based regimen. DESIGN: Multicenter, double-blind, randomized trial (NCT02652260). METHODS: Virologically suppressed adults receiving efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF), or its components, with ongoing EFV-associated CNS toxicity grade 2 or higher (DAIDS criteria) were switched to doravirine/lamivudine/tenofovir (DOR/3TC/TDF) on day 1 (Immediate Switch Group [ISG]) or after 12 weeks (Deferred Switch Group [DSG]). CNS toxicity data were collected by self-administered questionnaire. The primary endpoint was the proportion of participants with any grade 2 or higher CNS toxicity at week 12. Secondary endpoints included virologic response and effect on fasting lipids. RESULTS: Eighty-six participants (58% men, 56% black, median age 41 years, median 4 years on prior EFV regimen) were enrolled (43 ISG, 43 DSG) and included in the analyses. At week 12, 42% of ISG and 37% of DSG had at least 1 grade 2 or higher CNS toxicity [difference 4.7%, 95% CI (-16 to 25%); P = 0.33]. At 24 weeks postswitch, HIV-1 RNA less than 50 copies/ml was maintained in 95.3% of participants, and fasting lipids were significantly decreased (LDL-cholesterol -11.0, non-HDL-cholesterol -13.2, HDL-cholesterol -7.7, total cholesterol -20.9, and triglycerides -13.0 mg/dl). CONCLUSION: In participants who had CNS complaints while receiving EFV/FTC/TDF, improvement in CNS toxicities attributable to EFV was not significantly different after switching to DOR/3TC/TDF compared with remaining on EFV/FTC/TDF. Virologic efficacy was maintained and lipid profiles improved after switching to DOR/3TC/TDF.

Efficacy of caspofungin against invasive Candida or invasive Aspergillus infections in neutropenic patients.

BACKGROUND: Neutropenia is an indicator of poor prognosis in patients with fungal infections. All available clinical trial experience from the caspofungin development program was reviewed to ascertain the efficacy of caspofungin in neutropenic patients with documented invasive aspergillosis (IA) or invasive candidiasis (IC). METHODS: The review was limited to neutropenic patients with proven IC or proven/probable IA at caspofungin onset. Data were available from four clinical trials. All patients had an absolute neutrophil count < 500/mm(3) at the initiation of caspofungin. In all cases caspofungin was administered as monotherapy at a dose of 50 mg/day, after a 70-mg loading dose. In all patients efficacy was assessed at the completion of caspofungin therapy. Success included complete and partial responses. RESULTS: Sixty-eight neutropenic patients were identified with documented invasive infection, including 27 with IC and 41 with IA. Most patients had acute or chronic leukemia. A favorable response was noted in 63% (17 of 27 patients) of patients with IC, including a 58% (14 of 24 patients) response as first-line therapy and a 100% (3 of 3 patients) response as salvage therapy. Success in candidemia was 68% (17 of 25 patients). Outcomes across the different Candida species were similar. Favorable responses were noted in 39% (16 of 41 patients) of patients with IA, including a 42% (5 of 12 patients) response as first-line therapy and 38% (11 of 29 patients) response as salvage therapy. Success by site of IA was 40% for pulmonary (12 of 30 patients), 43% for sinus (3 of 7 patients), and 25% for skin/disseminated site (1 of 4 patients). CONCLUSIONS: A review of the caspofungin database demonstrates that this echinocandin is effective in neutropenic patients with documented cases of IC or IA.