Editor’s Note:
AIDS remains one of the most significant public health issues worldwide, with around 38 million people living with HIV (PLWH). In recent years, with the continuous advancement of antiretroviral therapy (ART), AIDS has gradually transformed into a manageable chronic disease. However, PLWH still face challenges like poor drug adherence and increased risk of resistance. Therefore, the development of innovative long-acting antiretroviral drugs has become a breakthrough to reduce the medication burden on patients and decrease the threat of the disease. From July 23 to 26, 2023, the 12th International AIDS Society HIV Science Conference (IAS 2023) was held in Brisbane, Australia. The latest research progress on long-acting HIV drugs became a major highlight of the conference. Infectious Disease Frontier specially invited Dr. Weiping Cai from the Eighth Affiliated Hospital of Guangzhou Medical University, China, to provide insightful comments on this hot research area.
Lenacapavir (LEN, brand name SUNLENCA) is the first long-acting HIV-1 capsid inhibitor. It regulates the stability and/or transport of the capsid complex, thus inhibiting multiple critical stages in the HIV replication cycle. LEN’s target is between the N-terminal domain (NTD) and C-terminal domain (CTD) of the capsid protein, directly binding to inhibit various key viral replication stages. The drug was approved in the EU in August 2022 and in the US in December of the same year. It’s used to treat adult HIV-1 patients with multidrug resistance (MDR) who cannot tolerate or safely undergo current ART. It’s often used in combination with other antiretroviral drugs.
Currently, LEN comes in two formulations: an injectable form administered subcutaneously (SC) every six months and an oral form taken once a week. Before maintaining a dose of 927 mg LEN via subcutaneous injection every six months, a lead-in regimen is required. If patients miss doses or fail to adhere to injections, it could lead to virologic failure and resistance.
At the recently concluded IAS 2023 conference, a study reported on the efficacy and safety of an oral bridging (OB) regimen for patients who couldn’t receive SC-LEN. This paper was co-authored by researchers from the US, Thailand, and France.
Figure 1. Research Design Flowchart
Figure 2. Baseline Characteristics of Patients
Results showed that patients suppressed at the OB baseline (HIV-1 RNA <50 copies/mL) maintained high viral suppression rates, and CD4+ cell counts remained stable or increased. Adverse reactions from OB were similar to SC, indicating good safety.
Figure 3. HIV Suppression Rate at Weeks 10, 20, and 30 after OB
Figure 4. Adverse Reaction Situations after OB
In addition, at the IAS 2023 conference, researchers from the United States and Italy reported on the Phase 2/3 clinical trials (CAPELLA study) of LEN treatment in AIDS patients with multi-drug resistance, focusing on the patient-reported outcomes (PROs) (Abstract EPB0216). The results of this study also provide a valuable supplement to the objective indicators such as laboratory results in the CAPELLA study. For this research, during the baseline and 52 weeks of treatment, a total of 5 validated scale scores were collected (Table 1), which are: European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) Index, EQ-5D-5L Visual Analog Scale (VAS), Short Form Health Survey (SF-36), HIV Symptom Index (HIV-si), and Numeric Pain Rating Scale (NPRS).
Table 1. The 5 validated scale scores adopted in PROs
Out of the 72 participants included in the study, data results were obtained for 64 of them at the 52-week mark. The PROs results show (Figure 5) that the number of participants with significant discomfort symptoms decreased significantly compared to baseline. Patients have a high acceptance of the LEN regimen of one subcutaneous (SC) injection every 6 months, which is consistent with the previously reported good safety profile and low discontinuation rate of LEN in the CAPELLA trial.
Figure 5. EQ-5D-5L, VAS, SF-36, HIV-si, and NPRS Situation of the five scale scores
Expert Review
LEN is the longest-acting drug on the market, featuring a unique mechanism of action, making it suitable for patients with multidrug-resistant HIV. It addresses challenges like poor adherence, privacy concerns related to daily medication, and feelings of shame. The above research shows that patients highly accept the six-month SC injection regimen of LEN, feeling significantly improved. The weekly oral substitution also offers a solution for those unable to receive regular injections, which could lead to uncontrolled HIV or even resistance. The oral transition regimen’s efficacy and safety are comparable to subcutaneous injection.
In the future, LEN’s indications may expand to first-line treatment and stable transition after HIV viral suppression without resistance, providing all HIV/AIDS patients with a more convenient, more effective, and safer ART treatment option.
References:
1. O. Ogbuagu, A. Avihingsanon, S. Segal-Maurer, et al. “Lenacapavir oral bridging maintains efficacy with a similar safety profile when SC LEN cannot be administered.” IAS 2023 Abstract OAB0205.
2. M. Ramgopal, D. Mezzio, K. Dunn, et al. “Participant-reported outcomes with long-acting lenacapavir-based regimens among heavily treatment-experienced people living with HIV in the CAPELLA clinical trial.” IAS 2023 Abstract EPB0216.
