1.
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.
Orkin, C, Squires, KE, Molina, JM, Sax, PE, Sussmann, O, Lin, G, Kumar, S, Hanna, GJ, Hwang, C, Martin, E, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021;(1):33-42
-
-
Free full text
-
Abstract
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.
2.
Identification of DNAH6 mutations in infertile men with multiple morphological abnormalities of the sperm flagella.
Tu, C, Nie, H, Meng, L, Yuan, S, He, W, Luo, A, Li, H, Li, W, Du, J, Lu, G, et al
Scientific reports. 2019;(1):15864
Abstract
Male infertility due to spermatogenesis defects affects millions of men worldwide. However, the genetic etiology of the vast majority remains unclear. Here we describe three men with primary infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) from two unrelated Han Chinese families. We performed whole-exome sequencing (WES) and Sanger sequencing on the proband of family 1, and found that he carried novel compound heterozygous missense mutations in dynein axonemal heavy chain 6 (DNAH6) that resulted in the substitution of a conserved amino acid residue and co-segregated with the MMAF phenotype in this family. Papanicolaou staining and transmission electron microscopy analysis revealed morphological and ultrastructural abnormalities in the sperm flagella in carriers of these genetic variants. Immunostaining experiments showed that DNAH6 was localized in the sperm tail. This is the first report identifying novel recessive mutations in DNAH6 as a cause of MMAF. These findings expand the spectrum of known MMAF mutations and phenotypes and provide information that can be useful for genetic and reproductive counseling of MMAF patients.
3.
Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial.
Orkin, C, Squires, KE, Molina, JM, Sax, PE, Wong, WW, Sussmann, O, Kaplan, R, Lupinacci, L, Rodgers, A, Xu, X, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;(4):535-544
-
-
Free full text
-
Abstract
BACKGROUND Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. METHODS DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). RESULTS Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (-1.6 vs +8.7 mg/dL and -3.8 vs +13.3 mg/dL, respectively). CONCLUSIONS In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF. CLINICAL TRIALS REGISTRATION NCT02403674.