Efficacy and safety of ainuovirine versus efavirenz combination therapies with lamivudine/tenofovir disoproxil fumarate for medication of treatment-naïve HIV-1-positive adults: week 48 results of a randomized controlled phase 3 clinical trial followed by an open-label setting until week 96

Bin Su; Guiju Gao; Min Wang; Yanqiu Lu; Linghua Li; Chen Chen; Yuanyuan Chen; Chuan Song; Fengting Yu; Ying Li; Yixin Liu; Yang Luo; Haolan He; Cong Cheng; Lixia Xu; Tong Zhang; Lijun Sun; An Liu; Wei Xia; Yuanyuan Qin; Qingxia Zhao; Hongxia Wei; Weiping Cai; Yaokai Chen; Fujie Zhang; Hao Wu

doi:10.1016/j.lanwpc.2023.100769

Efficacy and safety of ainuovirine versus efavirenz combination therapies with lamivudine/tenofovir disoproxil fumarate for medication of treatment-naïve HIV-1-positive adults: week 48 results of a randomized controlled phase 3 clinical trial followed by an open-label setting until week 96

Lancet Reg Health West Pac. 2023 Apr 24:36:100769. doi: 10.1016/j.lanwpc.2023.100769. eCollection 2023 Jul.

Authors

Bin Su¹, Guiju Gao², Min Wang³, Yanqiu Lu⁴, Linghua Li⁵, Chen Chen⁶, Yuanyuan Chen⁷, Chuan Song², Fengting Yu², Ying Li³, Yixin Liu³, Yang Luo⁴, Haolan He⁵, Cong Cheng⁶, Lixia Xu⁷, Tong Zhang¹, Lijun Sun¹, An Liu¹, Wei Xia¹, Yuanyuan Qin^{1

4}, Qingxia Zhao⁷, Hongxia Wei⁶, Weiping Cai⁵, Yaokai Chen⁴, Fujie Zhang², Hao Wu¹

Affiliations

¹ Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
² Clinical and Research Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
³ Institute of HIV/AIDS, The First Hospital of Changsha, Changsha, Hunan, 410005, China.
⁴ Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, 400036, China.
⁵ Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510060, China.
⁶ Department of Infectious Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China.
⁷ Department of Infectious Diseases, Infectious Disease Hospital of Henan Province, Zhengzhou, Henan, 450015, China.

Abstract

Background: Ainuovirine (ANV) is a new non-nucleoside reverse transcriptase inhibitor (NNRTI), which was initially synthesized in Korea and later further developed in both Korea and China.

Methods: A randomized, double-blind, double-dummy, positive parallel group, non-inferiority, phase 3 trial was conducted in 7 sites across China. Eligible HIV-1-positive antiretroviral therapy (ART)-naïve adults aged 18-65 years were randomly assigned in a 1:1 ratio to receive tenofovir disoproxil fumarate and lamivudine (TDF+3TC) in combination with either ANV (ANV group) or efavirenz (EFV group) for up to 48 weeks. Subsequently, participants in both groups received one of the two drug combinations according to their choice until week 96 in an observational study under an open-label setting. The primary endpoint was the proportion of participants achieving HIV RNA <50 copies/mL at week 48, with non-inferiority pre-specified at a margin of 10%. The secondary efficacy endpoints were logarithmic changes in HIV RNA, percentage of participants with HIV RNA levels ≤400 copies/mL and changes in the CD4 T-cell count after 48 and 96 weeks of treatment, as well as the percentage of participants with HIV RNA levels <50 copies/mL at 96 weeks of treatment. Safety endpoints were the incidence of adverse events and laboratory abnormalities evaluated according to the Division of AIDS criteria. This study was registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR1800019041).

Findings: Between November 27, 2018 and March 11, 2021, a total of 826 participants were screened, and 630 were finally enrolled and randomly assigned (1:1) to either ANV (n = 315) or EFV (n = 315) groups. The mean age was 30.6 ± 9.4 years and most participants were male (94.6%). At week 48, 274 (87.0%) of 315 participants in the ANV group and 288 (91.7%) of 314 in the EFV group achieved HIV-1 RNA <50 copies/mL and non-inferiority was established (difference: -4.7%, 95% CI: -9.6 to 0.1%). In the period, 293 participants continued to take the ANV regimen and 287 switched from the EFV to the ANV regimen. During the open-label period, 92.5% (271/293) of participants in the continued ANV group and 95.1% (273/287) in the ANV to EFV transfer group remained virologically suppressed (HIV-1 RNA <50 copies/mL) at week 96 (p = 0.189). The incidence of NNRTI treatment-related adverse events (TEAEs) at week 48 was 67.6% in 315 participants in the ANV group, which was significantly lower than in 91.4% of 314 participants in the EFV group (p < 0.001). The most common TEAEs (weeks 0-48) were dizziness (10.5%) and dyslipidemia (22.2%) in the ANV group vs. 51.0% and 34.4% in the EFV group, respectively, followed by transaminase elevation (9.2% vs. 29.0%), γ-glutamyl transferase elevation (8.3% vs. 19.1%), and rash (7.9% vs. 18.8%) (all p < 0.001). After switching from EFV to ANV, TEAEs in the former EFV participants were significantly reduced in the following observational period of 48-96 weeks.

Interpretation: The week 48 results indicated that the efficacy of ANV was non-inferior to EFV when combined with two NRTIs. The per-protocol risk difference at week 48 for the primary endpoint also supported non-inferiority. TEAEs in ANV treated participants were less frequent with regard to liver toxicity, dyslipidemia, neuropsychiatric symptoms and rash compared to the EFV group during the first 48 weeks of therapy. The effects were maintained during the 48-96 weeks of therapy.

Funding: Jiangsu Aidea Pharmaceutical Co., Ltd.

Keywords: Ainuovirine; Efficacy; HIV; NNRTI; Non-inferiority; Phase 3 clinical trial; Safety.