Safety and Efficacy of Long-Acting Injectable Agents for HIV-1：a systematic review and meta-analysis (Preprint)

BACKGROUND Human immunodeficiency virus-1 (HIV-1) infection continues to affect global health. Although antiretrovirals (ARVs) can reduce the viral load or prevent HIV infection, current drugs require daily oral use, requiring a high adherence level. Long-acting ARVs (LA-ARVs) can significantly improve medication adherence and play a vital role in HIV-1 prophylaxis and therapy. OBJECTIVE To investigate the safety and efficacy of LA-ARVs, particularly long-acting cabotegravir (CAB-LA) and long-acting rilpivirine (RPV-LA), in preventing and treating HIV-1 infection. METHODS PubMed, EMBASE, and Cochrane Library were searched for studies published between database inception and November 12, 2022. We extracted outcome data for analysis and expressed dichotomous data with risk ratios (RR) and continuous data with mean differences (MD). Depending on the heterogeneity assessment, a fixed-effects or random-effects model was used for data synthesis. We performed subgroup analyses of partial safety and efficacy outcomes for CAB-LA+RPV-LA and analyzed the results at different time points. RESULTS Twelve trials comprising 10,957 individuals were included in this meta-analysis. We found that the prophylactic drugs CAB-LA and RPV-LA had comparable safety profiles to placebo in the adverse event (AE)-related withdrawal. Moreover, efficacy data showed that CAB-LA had a better effect on HIV-1 prevention than tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) (0.33% [17/5161] vs. 1.46% [75/5129]; RR 0.21 [95% CI: 0.07-0.61]; I2=70%). Most infections in the CAB-LA group were due to undetectable plasma concentrations and low blood levels or occurred during the oral induction phase. Although CAB-LA+RPV-LA had more drug-related AEs (81.64% [556/681] vs. 6.19% [37/598]; RR 12.50 [95% CI: 3.98-39.23]; I2=85%), a mild or moderate injection site reaction (ISR) was the most common reaction, and its frequency decreased over time. Additionally, the percentage of individuals with plasma HIV-1 RNA less than 50 copies/ml (91.43% [1302/1424] vs. 92.15% [915/993]; RR 0.99 [95% CI: 0.97-1.02]; I2=0%) was comparable to oral drugs, and a high level of virological suppression of 80.87% (186/230) could be maintained even after the five years of CAB-LA+RPV-LA use. Those who switched from oral drugs to CAB-LA+RPV-LA also showed significant virological suppression (81.34% [436/536] vs. 95.74% [292/305]; RR 0.90 [95% CI: 0.79-1.03]; I2=85%) compared to those on long-term use of long-acting agents. CONCLUSIONS LA-ARVs all showed favorable safety profiles in both the prevention and treatment of HIV infection and were well tolerated. CAB-LA has more satisfactory efficacy than TDF-FTC, significantly reducing the rate of HIV infection. CAB-LA+RPV-LA maintains virological suppression for a long time and may be a viable switch strategy. Further trials are required to confirm the efficacy of these drugs. CLINICALTRIAL The protocol was registered with the Open Science Framework (10.17605/OSF.IO/ZNU6E).