Cost-effectiveness of efavirenz 600 mg vs. 400 mg in people living with HIV in China

Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), has been commonly used as a first-line therapy for HIV infection in China and worldwide. 1 However, its use has been associated with several side effects, including central nerous system disturbances, which can affect a patient’s quality of life and treatment adherence. 2 The potential benefits of reducing the standard dose of EFV from 600 mg daily to 400 mg have garnered attention in recent years, particularly regarding the decrease of adverse effects, maintaining therapeutic efficacy, and improving cost-effectiveness. 3, 4 Clinical trials, including the ENCORE1 study, 4 have indicated that a 400 mg daily dose of EFV is as effective as the standard 600 mg dose in suppressing the viral load in people living with human immunodeficiency virus (PLWH). In China, following such evidence, 5 the 400 mg dose was officially recommended in the national guidelines in China and worldwide. 6, 7 Lowering the EFV dose could reduce medication costs and improve quality-adjusted life years (QALYs), thereby improving the cost-effectiveness of HIV treatment regimens. 8 This can be particularly beneficial in resource-limited settings. We established a model of the progression of HIV infection in a Chinese population Figure 1A. Baseline stage distribution was derived from trial data Supplementary Table 1, https: //links. lww. com/CM9/C847. In HIV-negative patients, the infection rate was based on data from the Centers for Disease Control and Prevention in China Supplementary Table 2, https: //links. lww. com/CM9/C847. Infected patients were divided into four stages based on CD4+ T-cell counts, stage 1: CD4+ T-cell >500, stage 2: 350 500 cells/μL, HIV stage 2: 350 cells/μL <CD4+ T-cell ≤500 cells/μL, HIV stage 3: 200 cells/μL <CD4+ T-cell ≤350 cells/μL, HIV stage 4: CD4+ T-cell ≤200 cells/μL. (B) Cost-effectiveness frontier for treatment strategies. There are three different strategies: no treatment (circle), 400 mg EFV regimen (square), and 600 mg EFV regimen (triangle). This figure illustrates the cost and effectiveness of each strategy. ART: Antiretroviral therapy; EFV: Efavirenz; HIV: Human immunodeficiency virus; ICER: Incremental cost-effectiveness ratio; QALY: Quality-adjusted life years. After establishing the progression model and determining the adverse effect rates in both groups, we performed a cost-effectiveness analysis Figure 1B. The utilities for the different stages and side effects were obtained from the literature Supplementary Table 7, https: //links. lww. com/CM9/C847. The costs were divided into drug expenses, outpatient expenses, and hospitalization expenses. Drug expenses were calculated based on the government purchase prices. Outpatient and hospitalization expenses were obtained from the literature Supplementary Table 8, https: //links. lww. com/CM9/C847. Non-AIDS (stages I–III) and AIDS (stage IV) patients incurred different outpatient and hospitalization expenses. Based on the cost-effectiveness analysis, the “No treatment” strategy (122. 74; 28. 03 QALYs) served as the baseline. The “400 mg” regimen (256. 29; 28. 06 QALYs) yielded an incremental cost-effectiveness ratio (ICER) of 4325. 55 per QALY gained, indicating favorable cost-effectiveness compared with no treatment. In contrast, the “600 mg” regimen (264. 75; 28. 06 QALYs) produced a markedly higher ICER of 367, 214. 56 per QALY, suggesting substantially lower economic efficiency. Overall, the 400 mg dose demonstrated the most favorable cost-effectiveness profile. The tornado diagram of deterministic sensitivity analysis for the cost-effectiveness of treatment with 600 mg EFV vs. 400 mg EFV Supplementary Figure 1 and Supplementary Table 9, https: //links. lww. com/CM9/C847 demonstrated that EFV dose reduction remained a cost-effective strategy across wide variations in drug price, clinical efficacy, utility values, adverse event probabilities, monitoring costs, and HIV incidence rate. The drug price and efficacy assumptions exerted the most significant impact on ICER; however, the probability of cost-effectiveness consistently exceeded the conventional willingness-to-pay (WTP) thresholds (38, 223). These results confirmed the robustness of the economic advantage of EFV dose reduction. For the cost-effectiveness acceptability curves for all strategies within a WTP range of 0 to three times the per capita GDP, at the WTP threshold of 0. 5 times, one times, and three times the per capita GDP, the 400 mg treatment group showed 99%, 98%, and 89% probabilities of being cost-effective and outperforming other strategies, respectively. The analysis showed that EFV 400 mg consistently had the highest probability of being cost-effective across the relevant WTP thresholds, whereas EFV 600 mg was only cost-effective at higher thresholds Supplementary Figure 2, https: //links. lww. com/CM9/C847. We compared dizziness, depression, and poor sleep quality between the 600 mg and 400 mg EFV groups. Dizziness occurred in 8. 3% vs. 5. 4% of the patients (P = 0. 337), depression in 1. 5% vs. 3. 5% (P = 0. 370), and poor sleep in 29. 4% vs. 31. 0% (P = 0. 908). The rates were comparable with no significant differences, suggesting that a dose reduction to 400 mg does not increase adverse effects and may support its feasibility for cost savings. From 2018–2024, the number of PLWH on ART (718, 499 in 2018 to 1, 063, 303 in 2021) and EFV shows the rising number, reflecting expanded program coverage. The costs of both 600 mg and 400 mg EFV increased, but the 400 mg dose remained consistently cheaper. Switching from 600 to 400 mg resulted in cumulative savings of ~42. 7 million over 4 years Supplementary Table 10, https: //links. lww. com/CM9/C847. The rise in the number of PLWH on ART and EFV highlights expanded access to HIV treatment. Using 400 mg EFV achieved major cost savings without loss of efficacy, supporting dose optimization as a policy. Savings can strengthen treatment and prevention programs, whereas continued monitoring ensures that the outcomes remain comparable to those of the 600 mg group. Overall, adopting a lower dose conserves resources and broadens access to life-saving therapies. The importance of reducing the dose of EFV, a critical component in the treatment of HIV/AIDS, can be underscored from a clinical and economic perspective. From an economic standpoint, our analysis demonstrates that reducing the EFV dose from 600 to 400 mg yields substantial savings. Over 4 years, the cost reduction amounted to several million yuan annually, thereby providing significant budget relief. These resources can be reallocated to expand ART programs, strengthen infrastructure, or enhance support services, which is particularly meaningful in resource-limited settings where drug costs are a barrier to treatment access. 11, 12 Clinically, multiple studies have shown that EFV 400 mg maintains virological efficacy comparable to EFV 600 mg. 13 However, several limitations merit discussion. First, we acknowledge the potential temporal mismatch between 2018 trial enrollment and the 2019 national HIV incidence data used in our model. To address this, we conducted a deterministic sensitivity analysis varying the incidence rate by ± 20%, which did not materially change the results. Second, all trial participants had a body weight <60 kg, which may differ from the broader HIV-infected population. Given that low body weight is common in Chinese PLWH and EFV pharmacokinetics are weight-dependent, the findings remain highly relevant in this setting. However, extrapolation to heavier populations requires caution. Third, the model cycle length was 3 months, whereas the incidence of EFV-related adverse effects (AEs) may not be evenly distributed over time. However, the trial data indicated that the instantaneous incidence of AEs at 4 and 12 weeks was similar Supplementary Table 11, https: //links. lww. com/CM9/C847; our model, however, was based on cumulative incidence rates. Therefore, the potential bias introduced by the cycle length was likely to be minimal. Evidence for long-term EFV-related AEs remains limited. Fourth, in our model, treatment efficacy was represented by stage-specific transition probabilities based on our trial data rather than by direct resistance data Supplementary Table 3, https: //links. lww. com/CM9/C847, which indirectly captured the risk of virological failure over time. Although more granular, long-term resistance data would provide additional reassurance, the transition probability approach allows for dynamic modeling of treatment efficacy across different time horizons. Finally, ensuring the sustainability of HIV treatment programs is a critical global priority. Cost-saving measures can alleviate financial burdens. EFV dose reduction represents a pragmatic, evidence-based approach for optimizing HIV treatment regimens. It offers clinical non-inferiority, economic sustainability, and potential benefits in terms of patient quality of life, thereby supporting both national and global objectives in HIV care. Conflicts of interest None. Funding This study was supported by grants from the National Natural Science Foundation of China (No. 82273723), the Peking Union Medical College Hospital Central High-level Hospital Clinical Research Project (No. 2022-PUMCH-D-008), Chinese Academy of Medical Sciences Medical and Health Science and Technology Innovation Project (No. 2021-I2M-1-037), and “Thirteenth Five-Year Plan” National Science and Technology Major Project of China (No. 2017ZX10202101-001).