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. 2026 Jul 16;43(10):4646–4667. doi: 10.1007/s12325-026-03706-0

Real-World Safety and Effectiveness of Cabotegravir in People Living with HIV: Interim Report of a Post-marketing Surveillance in Japan

Yoichiro Yoshikawa 1,✉, Takako Nagao 2, Tomoko Matsukawa 1, Yuko Maeno 1, Akemi Sebata 1, Miwako Suzuki 1, Shiro Ibe 2, Akiko Fukuda 3, Dong Wang 2
PMCID: PMC13619692  PMID: 42461573

Abstract

Introduction

Cabotegravir (CAB) is an integrase strand transfer inhibitor and the first long-acting injectable antiretroviral agent for human immunodeficiency virus (HIV), administered with rilpivirine. Because approval in Japan relied largely on overseas and international collaborative trials, domestic real-world evidence remains limited. This study evaluated the real-world safety and effectiveness of CAB in people living with HIV (PLHIV) in Japan.

Methods

This interim analysis (June 27, 2022 and June 17, 2025) was part of an ongoing post-marketing surveillance of Japanese PLHIV treated with CAB at institutions participating in the HIV-related Drugs Cooperative Survey. Safety was assessed by the incidence of adverse drug reactions (ADRs). Associations between ADR incidence and background characteristics were examined using Fisher’s exact and χ2 tests without multiplicity adjustment. Effectiveness was evaluated using virologic suppression assessed by log-transformed HIV RNA copies/mL and peripheral CD4+ cell counts.

Results

A total of 121 and 117 participants were included in the safety and efficacy analysis sets, respectively; most were aged over 20 years, and over 96% were male participants. Overall, 76 ADRs were reported in 45 participants (37.19%). The most frequent ADRs were injection site pain and musculoskeletal pain (12.40% each). Four serious ADRs that were not explicitly deemed unrelated to CAB by the reporting physicians occurred in 4 participants: hepatitis B reactivation, monkeypox, syphilis, and type 2 diabetes mellitus. Stratification analyses by participant characteristics revealed high ADR incidences among participants aged ≥ 30 to < 40 years (p = 0.038), without allergy (p = 0.016), and with comorbidities (p = 0.045). HIV RNA copies remained suppressed and CD4+ cell counts were maintained at levels comparable to treatment initiation throughout follow-up.

Conclusion

This interim analysis indicates that CAB therapy is safe, with no new safety signals, and effective, as demonstrated by sustained virological suppression and stable CD4+ cell counts. These findings are consistent with outcomes reported in overseas and international collaborative clinical studies.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03706-0.

Keywords: Adverse drug reaction, Antiretroviral therapy, Cabotegravir, Effectiveness, HIV injectable treatment, Integrase strand transfer inhibitor, Interim analysis, Japan, Long-acting injectable treatment, Post-marketing product surveillance

Plain Language Summary

Taking multiple oral medications every day can be challenging for people living with human immunodeficiency virus (PLHIV). Cabotegravir, co-administered with rilpivirine, is the first long-acting injectable HIV treatment that can be given once monthly or every 2 months. Its approval in Japan was primarily based on overseas and international collaborative studies, and real-world clinical evidence in Japan has been limited. To address this gap, a post-marketing surveillance has been conducted to confirm the safety and effectiveness of cabotegravir in Japanese PLHIV. This was a 3-year interim analysis of post-marketing surveillance including 121 participants at 10 institutions in Japan who were virologically suppressed for over 6 months before switching to cabotegravir. During follow-up, 45 participants experienced 76 adverse drug reactions (37.19%) that included injection site pain and musculoskeletal pain (12.40% each), and oral herpes, high cholesterol, thickened or hardened injection site, fever, and decreased white blood cell counts (2.48% each). These findings were consistent with those reported in previous clinical studies. Higher adverse drug reaction rates were observed among participants aged ≥ 30 to < 40 years, those without allergy, and those with other medical conditions. Most adverse drug reactions considered related to cabotegravir occurred within 180 days after treatment initiation. Throughout the follow-up period, HIV RNA copies remained suppressed and CD4+ cell counts were maintained at levels similar to those at treatment initiation. Overall, these results confirm the real-world safety and effectiveness of cabotegravir in Japan.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03706-0.

Key Summary Points

Why carry out this study?
Cabotegravir (CAB) is the first long-acting injectable antiretroviral therapy administered monthly or every 2 months; however, its approval in Japan was based primarily on overseas and international collaborative clinical trials, resulting in limited domestic clinical evidence.
This interim analysis of post-marketing surveillance evaluated the real-world safety and effectiveness of CAB in people living with HIV (PLHIV) in Japan.
What was learned from the study?
Among 121 participants treated with CAB, 45 (37.19%) experienced adverse drug reactions, most commonly injection site pain and musculoskeletal pain, with no new safety signals identified.
HIV RNA copies remained suppressed, and peripheral CD4+ cell counts were maintained at baseline levels for up to 30–33 months following initiation of CAB treatment.
The findings confirm that the safety and effectiveness of CAB in routine clinical practice in Japan are consistent with results from previous overseas and international clinical studies.
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Introduction

The first cases of human immunodeficiency virus (HIV) infection were reported in 1981, followed by rapid global dissemination that led to a worldwide epidemic. In Japan, the earliest HIV-positive cases were identified in the early 1980s [1]. According to the Annual Report on AIDS Trends 2024, 662 new HIV infections and 332 new acquired immunodeficiency syndrome (AIDS) cases were reported in Japan in 2024, figures that are consistent with trends observed in previous years. Cumulatively, there have been 25,194 HIV infections and 11,181 AIDS cases reported in Japan, excluding cases associated with coagulation factor products [2]. Approximately 94% of reported HIV infection and AIDS cases in Japan have occurred in male patients.

Since the late 1990s, a treatment option for HIV has been antiretroviral therapy, which is a combination therapy consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one of integrase strand transfer inhibitor (INSTI), protease inhibitor, or non-nucleoside reverse transcriptase inhibitor (NNRTI) [3–6]. More recently, the two-drug regimen that consists of INSTI dolutegravir and NRTI lamivudine, has been added as one of the first treatment choices to reduce adverse drug reactions (ADRs) and to simplify dosing regimens [3, 4, 6]. Nevertheless, the need for daily oral administration of multiple agents and the occurrence of ADRs may negatively affect long-term treatment adherence [7–9]. Therefore, strategies that reduce medication burden and improve treatment compliance remain an important clinical objective.

Cabotegravir (CAB; Vocabria; ViiV Healthcare) is an INSTI and the first long-acting antiretroviral agent approved for the treatment of HIV infection in adults in Japan. CAB is available as a 30-mg oral tablet for short-term use, administered with oral rilpivirine (25 mg) prior to initiation of intramuscular (IM) therapy or to cover missed injections, as well as a long-acting aqueous suspension for IM at doses of 400 mg or 600 mg administered monthly or every 2 months. CAB is co-administered with the NNRTI rilpivirine (Edurant® and Rekambys®, Johnson & Johnson). CAB was first approved in Canada in March 2020 for monthly administration [10], followed by approval in Europe in December 2020 for monthly or every 2-month dosing [11]. In the United States, monthly dosing and every-2-month regimens were approved in January 2021 and February 2022, respectively [12]. In Japan, CAB was approved on May 31, 2022 [13–16], based primarily on overseas and international collaborative clinical studies that included 20 Japanese people living with HIV (PLHIV) and that demonstrated the safety and effectiveness of CAB in combination with rilpivirine [17–22]. As a result, real-world safety and effectiveness data in Japanese populations remain limited.

This study aimed to evaluate the safety and effectiveness of treatment with CAB in Japan. We report the approximately 3-year interim results from an on-going post-marketing surveillance.

Methods

Study Design

This post-marketing surveillance evaluating the safety and effectiveness of CAB in Japanese PLHIV has been ongoing since June 27, 2022, corresponding to the date when CAB first became commercially available in Japan, and is scheduled to continue until May 30, 2032, marking the end of the reexamination period for CAB. The present report represents an interim analysis including participants registered through June 17, 2025 (the data lock date). This surveillance is a part of the HIV-related drugs (HRD) Cooperative Survey in PLHIV, a nationwide joint research program conducted under the direction of the Ministry of Health, Labour and Welfare [23, 24]. Numerous HRD-participating institutions across Japan are involved, many of which specialize in HIV care and manage large populations of PLHIV. Eligible participants were individuals who had maintained virological suppression, defined as plasma HIV RNA < 50 copies/mL for more than 6 months, had no history of treatment failure, and had no known or suspected resistance to CAB or rilpivirine. Participants were enrolled through a centralized registration system.

This post-marketing surveillance was conducted by CMIC HOLDINGS Co., Ltd. (Tokyo, Japan) on behalf of ViiV Healthcare K.K. in compliance with applicable Japanese regulations, including the Ministerial Ordinance on Good Post-marketing Study Practice (GPSP; MHLW No. 171, December 20, 2004), its subsequent amendments, and related notifications. The study protocol was reviewed and approved by the Pharmaceuticals and Medical Devices Agency, the Japanese regulatory authority, and subsequently approved by the ethics committees of each participating institution. In accordance with GPSP regulations, written informed consent was not required for post-marketing surveillance; however, treating physicians provided participants with explanations regarding HIV treatment drugs, including antiretroviral drugs and other HIV-related medications, and obtained verbal consent prior to participation.

Treatment

Participants received oral CAB at a dose of 30 mg once daily in combination with oral rilpivirine 25 mg, administered with a meal, for approximately 1 month (at least 28 days) prior to initiation of injectable therapy to assess the tolerability [13–16]. Treatment was then transitioned to IM gluteal injections of CAB and rilpivirine administered either monthly or every 2 months. On the final day of oral CAB administration, a 600-mg dose of injectable CAB was given, followed by either bi-monthly injections of 600 mg CAB or monthly injections of 400 mg CAB, beginning 1 month after the initial 600-mg injection.

Study Variables

The following data were collected: participant demographics and disease characteristics (sex, race, status of pregnancy, inpatient or outpatient status, date of birth or age, height, route of HIV infection, primary disease, time of infection, comorbidities, and medical history), status of treatment with anti-HIV drugs (history of anti-HIV drug prescription and treatment start date; combination and duration of anti-HIV drugs before switching to CAB, drug names, dose, administration start date, status of administration, reasons for changes in administration intervals, reasons for discontinuation of administration [in case the reason for discontinuation was due to insufficient effectiveness or drug resistance, results of genotypic testing for drug resistance were also collected if the genotypic test was conducted], prescribed concomitant drugs other than anti-HIV drugs (history of prescribed concomitant drugs, drug names, administration start date, status of administration, reasons for the administration of drugs), adverse events (diagnosis or symptoms, dates of onset and outcome, outcomes, seriousness, reasons for being judged as serious, causal relationships, symptoms, clinical course, treatment, and laboratory test values related to the adverse event if available), log-transformed plasma HIV RNA copies, peripheral CD4+ cell counts, and body weight. Note that allergies recorded as comorbidities reflected a medical history of allergy and were not specific to CAB or rilpivirine; details regarding the types of these allergies, such as food, environmental, or drug-related, were not distinguished.

Statistical Analyses

The ADRs were analyzed in the safety analysis set, in which all participants who received CAB were included, excluding those who did not return for follow-up after the initial visit or for whom adverse event follow-up was not possible. The effectiveness was analyzed in the effectiveness analysis set which excluded participants treated with CAB for indications not specified in the package insert and those lacking both pre-treatment and post-treatment for HIV RNA copies and CD4+ cell counts.

In this surveillance, ADRs were defined as adverse events suspected of being related to the use of CAB. When assessments differed between the reporting physician and the sponsor, the more severe evaluation was adopted. Similarly, when classifications of seriousness differed, the more severe classification was used. Adverse events and ADRs were coded according to preferred terms using the Japanese version of the Medical Dictionary for Regulatory Activities Japanese version 27.1. Categorical variables were summarized as numbers and percentages. The participant characteristics (sex, and presence or absence of concomitant drugs, renal disorders, liver disorders and comorbidities) with relationship to the incidence of ADRs were identified using the Fisher’s exact test or χ2 test without multiplicity adjustment. Missing data were not imputed. All statistical analyses were carried out using SAS version 9.4 (SAS Institute).

Results

Participant Disposition and Characteristics

Among 21 HRD participating institutions, survey forms were collected from 121 participants (safety analysis set) at 10 institutions between June 27, 2022 and June 17, 2025 (Fig. 1). Because 4 participants had no record of HIV RNA copies or CD4+ cell counts at both pre-treatment and post-treatments, 117 participants were included in the effectiveness analysis set. Participant characteristics are summarized in Table 1. Of the 121 participants, more than 96% were male participants. Age distribution was as follows: one participant (0.83%) was aged ≥ 10– < 20 years, 12 (9.92%) were aged ≥ 20– < 30 years, 44 (36.36%) were aged ≥ 30– < 40 years, 34 (28.10%) were aged ≥ 40– < 50 years, 21 (17.36%) were aged ≥ 50– < 60 years, 7 (5.79%) were aged ≥ 60– < 70 years, and 2 (1.65%) were aged ≥ 70 years in the safety analysis set. No pregnant women were included in the surveillance. More than 97% of participants acquired HIV through sexual transmission, and the duration of HIV infection was unknown or unrecorded in a majority of participants (87.60%). Comorbidities were reported in 58.68% of participants, allergies in 9.09%, liver disorder in 8.26% and renal disorder in 4.13%, whereas no participant had hemophilia. All participants received rilpivirine in combination with CAB, and no participant was treated with CAB alone. In all participants, injectable CAB and rilpivirine were administered every 2 months. Baseline characteristics of participants in the effectiveness analysis set were similar to those of the safety analysis set.

Fig. 1.

Fig. 1

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Participant disposition. HIV human immunodeficiency virus, RNA ribonucleic acid

Table 1.

Participant characteristics

Characteristics Safety analysis set
n (%)		 Effectiveness analysis set
n (%)
Number of participants – 121 117
Sex Male 117 (96.69) 113 (96.58)
Female 4 (3.31) 4 (3.42)
Pregnancy No 4 (100.00) 4 (100.00)
Yes 0 (0.00) 0 (0.00)
Race Japanese 114 (94.21) 110 (94.02)
Other 7 (5.79) 7 (5.98)
In/out patients Inpatient 0 (0.00) 0 (0.00)
Outpatient 116 (95.87) 112 (95.73)
Inpatient/outpatient 5 (4.13) 5 (4.27)
Age category (1), year  < 15 1 (0.83) 1 (0.85)
 ≥ 15– < 65 118 (97.52) 114 (97.44)
 ≥ 65 2 (1.65) 2 (1.71)
Age category (2), year  < 10 0 (0.00) 0 (0.00)
 ≥ 10– < 20 1 (0.83) 1 (0.85)
 ≥ 20– < 30 12 (9.92) 11 (9.40)
 ≥ 30– < 40 44 (36.36) 43 (36.75)
 ≥ 40– < 50 34 (28.10) 33 (28.21)
 ≥ 50– < 60 21 (17.36) 21 (17.95)
 ≥ 60– < 70 7 (5.79) 6 (5.13)
 ≥ 70 2 (1.65) 2 (1.71)
Number of participants 121 117
Mean 41.7 41.7
SD 11.0 10.8
Min 14 14
Max 80 80
Route of infection Sexual transmission 118 (97.52) 114 (97.44)
Mother-to-child transmission 2 (1.65) 2 (1.71)
Unknown/not recorded 1 (0.83) 1 (0.85)
Blood products 0 (0.00) 0 (0.00)
Medical accident 0 (0.00) 0 (0.00)
Other 0 (0.00) 0 (0.00)
Primary disease HIV infection 121 (100.00) 117 (100.00)
Other 0 (0.00) 0 (0.00)
Duration of disease, years  ≤ 1 2 (1.65) 2 (1.71)
 > 1– ≤ 2 0 (0.00) 0 (0.00)
 > 2– ≤ 3 2 (1.65) 2 (1.71)
 > 3– ≤ 4 0 (0.00) 0 (0.00)
 > 4– ≤ 5 1 (0.83) 1 (0.85)
 > 5 10 (8.26) 10 (8.55)
Unknown/not recorded 106 (87.60) 102 (87.18)
Number of participants 15 15
Min 1 1
Max 23 23
Medical history No 50 (41.32) 47 (40.17)
Yes 27 (22.31) 26 (22.22)
Unknown/not recorded 44 (36.36) 44 (37.61)
Allergy No 103 (85.12) 100 (85.47)
Yes 18 (14.88) 17 (14.53)
Comorbidities No 31 (25.62) 29 (24.79)
Yes 71 (58.68) 69 (58.97)
Unknown/not recorded 19 (15.70) 19 (16.24)
Types of comorbiditya Allergy 11 (9.09) 10 (8.55)
Liver disorder 10 (8.26) 10 (8.55)
Hypertension 6 (4.96) 6 (5.13)
Renal disorder 5 (4.13) 5 (4.27)
Syphilis 3 (2.48) 3 (2.56)
Diabetes 0 (0.00) 0 (0.00)
Hemophilia 0 (0.00) 0 (0.00)
Other 59 (48.76) 57 (48.72)
Hemophilia No 121 (100.00) 117 (100.00)
Yes 0 (0.00) 0 (0.00)
A 0 (–) 0 (–)
B 0 (–) 0 (–)
Renal disorder No 115 (95.04) 111 (94.87)
Yes 5 (4.13) 5 (4.27)
Unknown/not recorded 1 (0.83) 1 (0.85)
Liver disorder No 74 (61.16) 70 (59.83)
Yes 10 (8.26) 10 (8.55)
Unknown/not recorded 37 (30.58) 37 (31.62)
History of anti-HIV drug prescription No 0 (0.00) 0 (0.00)
Yes 121 (100.00) 117 (100.00)
Treatment duration, days  ≤ 180 16 (13.22) 12 (10.26)
 > 180– ≤ 365 15 (12.40) 15 (12.82)
 > 365– ≤ 730 53 (43.80) 53 (45.30)
 > 730 36 (29.75) 36 (30.77)
Unknown/not recorded 1 (0.83) 1 (0.85)
Number of participants 120 116
Min 1 1
Max 1003 1003
Cumulative treatment duration, days  ≤ 180 120 (99.17) 116 (99.15)
 > 180– ≤ 365 104 (85.95) 104 (88.89)
 > 365– ≤ 730 89 (73.55) 89 (76.07)
 > 730 36 (29.75) 36 (30.77)
Unknown/not recorded 1 (0.83) 1 (0.85)
Total dose, mg  ≤ 3000 16 (13.22) 12 (10.26)
 > 3000– ≤ 5400 26 (21.49) 26 (22.22)
 > 5400– ≤ 10,200 67 (55.37) 67 (57.26)
 > 10,200 11 (9.09) 11 (9.40)
Unknown/not recorded 1 (0.83) 1 (0.85)
Number of participants 120 116
Min 30 30
Max 11,910 11,910
Cumulative total dose, mg  ≤ 3000 120 (99.17) 116 (99.15)
 > 3000– ≤ 5400 104 (85.95) 104 (88.89)
 > 5400– ≤ 10,200 78 (64.46) 78 (66.67)
 > 10,200 11 (9.09) 11 (9.40)
Unknown/not recorded 1 (0.83) 1 (0.85)
Concomitant drugs other than rilpivirine No 52 (42.98) 50 (42.74)
Yes 69 (57.02) 67 (57.26)
Number of concomitant drugs  ≤ 2 52 (42.98) 50 (42.74)
 ≥ 3– ≤ 5 44 (36.36) 42 (35.90)
 ≥ 6 25 (20.66) 25 (21.37)
Type of concomitant drugsa Anti-HIV drugs 121 (100.00) 117 (100.00)
Other antivirals 4 (3.31) 4 (3.42)
Other 68 (56.20) 66 (56.41)
Number of concomitant anti-HIV drugsb Monotherapy 0 (0.00) 0 (0.00)
1 4 (3.31) 2 (1.71)
2 117 (96.69) 115 (98.29)
3 0 (0.00) 0 (0.00)
 ≥ 4 0 (0.00) 0 (0.00)
Type of concomitant anti-HIV drugsa Non-nucleoside reverse transcriptase inhibitors 121 (100.00) 117 (100.00)
CCR5 inhibitors 0 (0.00) 0 (0.00)
Integrase inhibitors 0 (0.00) 0 (0.00)
Nucleoside reverse transcriptase inhibitors 0 (0.00) 0 (0.00)
Protease inhibitors 0 (0.00) 0 (0.00)
Blood coagulation factor No 121 (100.00) 117 (100.00)
Yes 0 (0.00) 0 (0.00)
Blood coagulation factor in participants with comorbid hemophilia No 0 (–) 0 (–)
Yes 0 (–) 0 (–)
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Data are presented as n (%) unless otherwise indicated

CCR5 CC-chemokine receptor 5, HIV human immunodeficiency virus, SD standard deviation

aMultiple selections permitted

bAlthough Edurant® and IM Rekambys® are both rilpivirine, they were counted separately

Safety Analysis

Overall, 76 ADRs, including injection site reactions, were reported in 45 of 121 participants (37.19%) (Supplementary Table S1). The most common ADRs were injection site pain and musculoskeletal pain (reported as buttock pain by the reporting physician in all cases), reported in 12.40% (15/121) each of participants. Other ADRs reported in ≥ 2 participants included oral herpes, dyslipidemia, injection site induration, pyrexia, and white blood cell count decreased in 2.48% (3/121) each of participants, as well as acne and injection site reaction in 1.65% (2/121) each of participants. Four serious ADRs, hepatitis B reactivation (not resolved), monkeypox (recovered), syphilis (improved), and type 2 diabetes mellitus (improved), occurred in four participants.

Stratified analyses identified differences in ADR incidence according to age, allergy status, and presence of comorbidities (Table 2). ADR incidence was highest among participants aged ≥ 30– < 40 years (54.55%, 24/44; p = 0.038). A difference was found in the incidence of ADRs between participants without allergy (41.75%, 43/103) and those with allergy (11.11%, 2/18; p = 0.016). A difference was also found for the presence or absence of comorbidities (present in 45.07%, 32/71; absent in 22.58%, 7/31; p = 0.045).

Table 2.

Incidence of ADRs by participant characteristics

Characteristics Number of participants Number of participants with ADRs (%) Number of ADRs p valuea
Overall – 121 45 (37.19) 76 –
Sex Male 117 45 (38.46) 76 0.296
Female 4 0 (0.00) 0
Pregnancy No 4 0 (0.00) 0 –
Yes 0 0 (–) 0
Race Japanese 114 42 (36.84) 72 0.710
Other 7 3 (42.86) 4
In/out patients Inpatient 0 0 (–) 0 0.156
Outpatient 116 45 (38.79) 76
Inpatient/outpatient 5 0 (0.00) 0
Age category (1), year  < 15 1 0 (0.00) 0 0.402b
 ≥ 15– < 65 118 45 (38.14) 76
 ≥ 65 2 0 (0.00) 0
Age category (2), year  < 10 0 0 (–) 0 0.038b
 ≥ 10– < 20 1 0 (0.00) 0
 ≥ 20– < 30 12 4 (33.33) 7
 ≥ 30– < 40 44 24 (54.55) 39
 ≥ 40– < 50 34 12 (35.29) 25
 ≥ 50– < 60 21 5 (23.81) 5
 ≥ 60– < 70 7 0 (0.00) 0
 ≥ 70 2 0 (0.00) 0
Route of infection Sexual transmission 118 45 (38.14) 76 0.527
Mother-to-child transmission 2 0 (0.00) 0
Unknown/not recorded 1 0 (0.00) 0
Blood products 0 0 (–) 0
Medical accident 0 0 (–) 0
Other 0 0 (–) 0
Primary disease HIV infection 121 45 (37.19) 76 –
Other 0 0 (–) 0
Duration of disease, years  ≤ 1 2 0 (0.00) 0 0.100b
 > 1– ≤ 2 0 0 (–) 0
 > 2– ≤ 3 2 1 (50.00) 3
 > 3– ≤ 4 0 0 (–) 0
 > 4– ≤ 5 1 1 (100.00) 1
 > 5 10 1 (100.00) 2
Unknown/not recorded 106 42 (39.62) 70
Medical history No 50 14 (28.00) 19 1.000
Yes 27 8 (29.63) 12
Unknown/not recorded 44 23 (52.27) 45
Allergy No 103 43 (41.75) 72 0.016
Yes 18 2 (11.11) 4
Comorbidities No 31 7 (22.58) 8 0.045
Yes 71 32 (45.07) 56
Unknown/not recorded 19 6 (31.58) 12
Types of comorbidityc Allergy 11 2 (18.18) 4 –
Liver disorder 10 2 (20.00) 3
Hypertension 6 1 (16.67) 3
Renal disorder 5 1 (20.00) 1
Syphilis 3 0 (0.00) 0
Diabetes 0 0 (–) 0
Hemophilia 0 0 (–) 0
Other 59 30 (50.85) 51
Hemophilia No 121 45 (37.19) 76 –
Yes 0 0 (–) 0
A 0 0 (–) 0 –
B 0 0 (–) 0
Renal disorder No 115 44 (38.26) 75 0.649
Yes 5 1 (20.00) 1
Unknown/not recorded 1 0 (0.00) 0
Liver disorder No 74 16 (21.62) 21 1.000
Yes 10 2 (20.00) 3
Unknown/not recorded 37 27 (72.97) 52
History of anti-HIV drug prescription No 0 0 (–) 0 –
Yes 121 45 (37.19) 76
Cumulative treatment duration, days  ≤ 180 120 41 (34.17) 60 –
 > 180– ≤ 365 104 0 (0.00) 6
 > 365– ≤ 730 89 2 (2.25) 6
 > 730 36 0 (0.00) 1
Unknown/not recorded 1 2 (–) 3
Cumulative total dose, mg  ≤ 3000 120 40 (33.33) 61 –
 > 3000– ≤ 5400 104 2 (1.92) 6
 > 5400– ≤ 10,200 78 1 (1.28) 6
 > 10,200 11 0 (0.00) 0
Unknown/not recorded 1 2 (–) 3
Concomitant drugs other than rilpivirine No 52 14 (26.92) 20 0.057
Yes 69 31 (44.93) 56
Number of concomitant drugs  ≤ 2 52 14 (26.92) 20 0.084b
 ≥ 3– ≤ 5 44 18 (40.91) 29
 ≥ 6 25 13 (52.00) 27
Type of concomitant drugsc Anti-HIV drugs 121 45 (37.19) 76 –
Other antivirals 4 4 (100.00) 10
Other 68 30 (44.12) 52
Number of concomitant anti-HIV drugsd Monotherapy 0 0 (–) 0 1.000
1 4 1 (25.00) 1
2 117 44 (37.61) 75
3 0 0 (–) 0
 ≥ 4 0 0 (–) 0
Type of concomitant anti-HIV drugsc Non-nucleoside reverse transcriptase inhibitors 121 45 (37.19) 76 –
CCR5 inhibitors 0 0 (–) 0
Integrase inhibitors 0 0 (–) 0
Nucleoside reverse transcriptase inhibitors 0 0 (–) 0
Protease inhibitors 0 0 (–) 0
Blood coagulation factor No 121 45 (37.19) 76 –
Yes 0 0 (–) 0
Blood coagulation factor in participants with comorbid hemophilia No 0 0 (–) 0 –
Yes 0 0 (–) 0
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ADR adverse drug reaction, CCR5 CC-chemokine receptor 5, HIV human immunodeficiency virus

aFisher’s exact test unless otherwise indicated

bχ2 test

cMultiple selections permitted

dAlthough Edurant® and IM Rekambys® are both rilpivirine, they were counted separately

Five participants with renal disorders received CAB; one developed musculoskeletal pain (20.00%, 1/5), and no serious ADR was reported in this subgroup. Among 10 participants with liver disorders, two experienced ADRs (20.00%, 2/10): hepatitis B reactivation in one participant and nausea and vomiting in another. CAB treatment was discontinued in the participants with hepatitis B reactivation but was continued in the participant who experienced nausea and vomiting.

The occurrence of ADRs by cumulative duration of treatment with CAB is presented in Table 3. Most ADRs occurred within the first year of treatment. After 1 year of CAB therapy, two events each of dyslipidemia and white blood cell count decrease, and one event each of androgenetic alopecia, gastroesophageal reflux disease, and syphilis were reported. Dyslipidemia and white blood cell count decreased were also reported within the first year of treatment. Because androgenetic alopecia, gastroesophageal reflux disease, and syphilis are not typical ADRs associated with long-term CAB therapy, no specific pattern of ADRs related to prolonged CAB exposure was identified.

Table 3.

Incidence of ADRs by duration of treatment with CAB

Days from start of treatment to occurrence of ADR
 ≤ 180
(n = 120)		  > 180– ≤ 365
(n = 104)		  > 365– ≤ 730
(n = 89)		  > 730
(n = 36)
Preferred term Number of events Number of participants (%) Number of events Number of participants (%) Number of events Number of participants (%) Number of events Number of participants (%)
Participants with ADR 60 41 (34.17) 6 5 (4.81) 6 5 (5.62) 1 1 (2.78)
Injection site pain 15 15 (12.50) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Musculoskeletal pain 14 14 (11.67) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Injection site induration 3 3 (2.50) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Oral herpes 3 3 (2.50) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Pyrexia 3 3 (2.50) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Acne 2 2 (1.67) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Abdominal pain upper 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Diarrhoea 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Dyslipidaemia 1 1 (0.83) 0 0 (0.00) 2 2 (2.25) 0 0 (0.00)
Gastritis 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Haemorrhage subcutaneous 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Hepatitis B DNA increased 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Hepatitis B reactivation 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Injection site reaction 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Malaise 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Monkeypox 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Nausea 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Pharyngitis 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Seasonal allergy 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Seborrhoeic dermatitis 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Somnolence 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Treatment noncompliance 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Type 2 diabetes mellitus 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Urticaria 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
Vomiting 1 1 (0.83) 0 0 (0.00) 0 0 (0.00) 0 0 (0.00)
White blood cell count decreased 1 1 (0.83) 0 0 (0.00) 2 2 (2.25) 0 0 (0.00)
Androgenetic alopecia 0 0 (0.00) 0 0 (0.00) 1 1 (1.12) 0 0 (0.00)
Asthma 0 0 (0.00) 1 1 (0.96) 0 0 (0.00) 0 0 (0.00)
Back pain 0 0 (0.00) 1 1 (0.96) 0 0 (0.00) 0 0 (0.00)
COVID-19 0 0 (0.00) 1 1 (0.96) 0 0 (0.00) 0 0 (0.00)
Gastroesophageal reflux disease 0 0 (0.00) 0 0 (0.00) 0 0 (0.00) 1 1 (2.78)
Hyperventilation 0 0 (0.00) 1 1 (0.96) 0 0 (0.00) 0 0 (0.00)
Myalgia 0 0 (0.00) 1 1 (0.96) 0 0 (0.00) 0 0 (0.00)
Mycoplasma urethritis 0 0 (0.00) 1 1 (0.96) 0 0 (0.00) 0 0 (0.00)
Syphilis 0 0 (0.00) 0 0 (0.00) 1 1 (1.12) 0 0 (0.00)
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MedDRA/J version 27.1

ADR adverse drug reactions, CAB cabotegravir, HIV human immunodeficiency virus

Effectiveness Analysis

HIV RNA copies remained suppressed at levels comparable to those at treatment initiation throughout the observation period (Fig. 2). The CD4+ cell counts were also maintained at levels similar to that at the start of treatment (Fig. 3).

Fig. 2.

Fig. 2

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Plasma HIV RNA copies for up to 33 months after the start of treatment with CAB. The data were log-transformed and are presented as mean ± SD. CAB cabotegravir, HIV human immunodeficiency virus, RNA ribonucleic acid, SD standard deviation

Fig. 3.

Fig. 3

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Peripheral CD4+ cell counts up to 33 months after the start of treatment with CAB. Data are presented as mean ± SD. CAB cabotegravir, HIV human immunodeficiency virus, SD standard deviation

Discussion

In Japan, CAB was approved for the treatment of HIV infection in 2022, primarily on the basis of evidence from overseas clinical and international collaborative studies and, therefore, clinical evidence for the safety and effectiveness of CAB in Japan have been limited [25, 26]. Here, in this 3-year interim analysis of post-marketing surveillance, we report the real-world evidence by evaluating the safety and effectiveness of CAB in 121 Japanese PLHIV.

Participants included in this surveillance were enrolled through institutions participating in the HRD Cooperative Survey. Overall, the demographic and clinical characteristics of the study population were comparable to those reported for PLHIV in Japan [2]. The vast majority of participants (97%) were male, consistent with national epidemiological data from the Annual Report on AIDS Trends in Japan, indicating that the sex distribution in this surveillance reflects real-world patterns of HIV infections in Japan. Because HIV infection is disproportionately reported among men, the limited representation of women precluded meaningful assessment of sex-specific differences in the safety or effectiveness of CAB. Similarly, the distributions of age, race, and route of infection, with most participants aged 20–49 years and infected primarily through sexual transmission, were consistent with national surveillance data. Collectively, these findings support the representativeness of the study population with respect to the broader Japanese PLHIV population.

Injection site-related events are well recognized as common ADRs associated with CAB injections [17–22, 27]. In the present surveillance, the incidence of musculoskeletal pain was as high as that of injection site pain. Notably, all reported musculoskeletal pain events were described as buttock pain, suggesting that these events were likely injection site-related. It has been reported that the incidence of injection site-related events decreases with repeated administrations and that treatment satisfaction improves over time with CAB therapy [28]. Therefore, although approximately one in eight participants experienced injection site pain, these events do not appear to be clinically significant in terms of negatively affecting treatment adherence or overall satisfaction.

Four serious ADRs were reported during surveillance, and, in each case, the reporting physicians did not explicitly exclude a potential causal relationship with CAB. However, there was no evidence to suggest a novel or previously unrecognized causal association between CAB and any of these events. Importantly, the overall incidence and pattern of ADRs observed in this interim analysis were comparable to those reported in prior clinical trials, and no new safety signals, including those related to injection site reactions, were identified.

Subgroup analyses demonstrated higher incidences of ADRs among participants aged ≥ 30– < 40 years, those with no allergy, and those with comorbidities. In this surveillance, multiplicity adjustments have not been performed, and, for example, there may be cases where the majority of participants belong to an age group with significant differences or where there is an imbalance in the numbers between the two groups. For the high incidence of ADRs among participants aged ≥ 30– < 40 years, it is plausible that such an age-group-specific high incidence of ADRs might have been caused by the large number of participants and characteristics unique to participants in this age group. Furthermore, the small sample size and potential confounding variables, such as different information obtained as part of routine clinical practice across institutions, might have affected the allergy-related outcomes. Therefore, these findings should be interpreted with caution. We did not find clear associations between ADR types and age group or allergy status, and the underlying mechanisms for these observed differences remain unclear (Supplementary Tables S2 and S3). With respect to comorbidities, the high ADR incidence was likely associated with concomitant medications used to manage HIV and/or other health conditions. Given that nearly 60% of participants had comorbidities, the absence of details about concomitant medication use limited the ability to identify specific drug-related contributors to ADR occurrence.

Treatment with CAB has rarely been associated with hepatotoxicity, regardless of the presence of comorbid liver disorder or its risk factors. In the present surveillance, two participants with liver dysfunction experienced three ADRs; however, given the limited number of cases, it was difficult to determine a clear pattern or trend in ADR occurrence within this subgroup. Therefore, no specific tendency for ADRs has been confirmed in participants with liver dysfunction. Similarly, owning the small sample size with low incidence of ADRs, we did not find a specific tendency toward the development of renal disorders in patients with or without pre-existing renal disease.

To further evaluate potential long-term safety concerns, ADRs were examined according to cumulative duration of CAB treatment. Although the sample size was limited, interim analyses demonstrated that the majority of ADRs occurred within 180 days of treatment initiation. There included 15 events of injection site pain, 14 of musculoskeletal pain, 3 of injection site induration, and 1 injection site reaction. Beyond 180 days of treatment, the incidence of ADRs decreased substantially. After 1 year of CAB therapy, only one or two events each of dyslipidemia, white blood cell count decrease, androgenetic alopecia, gastroesophageal reflux disease, and syphilis were reported. Of note, dyslipidemia and white blood cell count decreased were also reported within 180 days of the treatment. Because androgenetic alopecia, gastroesophageal reflux disease, and syphilis are not specifically associated with the long-term treatment with CAB, no consistent pattern of ADRs related to long-term CAB treatment was identified.

All participants included in this surveillance were virologically suppressed prior to switching to CAB as instructed in the package inserts [13–16]. After switching to CAB, HIV RNA copies remained suppressed at baseline levels throughout the 3-year surveillance period. Furthermore, CD4+ cell counts were maintained at the baseline levels. These effectiveness outcomes are consistent with those reported at 48–96 weeks and up to 152 weeks in previous overseas clinical studies, further confirming the effectiveness of CAB in Japanese participants [18, 19, 21, 27].

There are some limitations in this interim report. First, it was a post-marketing surveillance with no control arm. Second, participants were enrolled from 10 institutions, where consent for disclosing information was obtained, among those participating in the HRD Cooperative Survey and, therefore, there may be a selection bias in this population. However, as discussed previously, the study population closely reflects the broader population of PLHIV in Japan. Third, the sample size of PLHV during the 24–36 months of the observation period in the effectiveness dataset lacked sufficient statistical power. However, considering that the long-term data in Japan have been limited, we believe that presenting such data, although collected from a small sample, is significant. Fourth, all adverse events for which the reporting physician has not ruled out a causal relationship with CAB, including those of unknown relationship, have been tabulated as ADRs. Fifth, ADRs reported in this surveillance were combined outcomes of anti-HIV drugs as well as medications for diseases other than HIV, rather than those attributable solely to CAB. Sixth, laboratory assessments were not obtained at all time points because the data were collected under real-world clinical conditions, resulting in missing data. Despite such limitations, the results of this surveillance provide valuable real-world insights into the safety and effectiveness of CAB in Japan.

In summary, the present 3-year interim analyses demonstrate that CAB therapy is associated with ADRs consistent with those previously reported, with no evidence of new safety concerns, and is effective in maintaining durable viral suppression and immune function comparable to levels observed at the time of switching to CAB. These findings align with results from overseas and international collaborative studies. As the first long-acting injectable antiretroviral agent with demonstrated effectiveness and an established safety profile, CAB offers a treatment approach that differs fundamentally from daily oral regimens. Monthly or every-2-month administration may reduce the psychological burden associated with daily medication use and thereby improve treatment satisfaction and adherence, as supported by recent studies [29–32]. Furthermore, CAB may represent a particularly useful treatment option for PLHIV who experience difficulty with daily oral medication, including older adults and individuals with cognitive impairment.

Conclusion

This 3-year interim analysis of post-marketing surveillance confirmed the safety and effectiveness of CAB under real-world clinical conditions in Japan that are consistent with those reported in previous overseas and international collaborative clinical studies. No new safety signals were identified. Although this was an interim report with a limited number of participating institutions, it reports a relatively large-scale dataset comprising over 100 participants, indicating the clinical significance of our study given that real-world clinical evidence of CAB in Japan is limited. The results are expected to be further verified upon completion of the on-going 10-year post-marketing surveillance.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 304 KB) (303.9KB, pdf)

Acknowledgements

The authors would like to thank all participating physicians, associated healthcare professionals, and individuals who took part in this post-marketing surveillance. The authors also acknowledge Tomoyuki Watanabe, a former employee of ViiV Healthcare K.K., for his valuable contributions and insightful input during the development of this manuscript.

Medical Writing, Editorial, and Other Assistance

Medical writing and English editing support were provided by ASCA Corp. and funded by ViiV Healthcare K.K.

Author Contributions

Yoichiro Yoshikawa and Takako Nagao led conception and design of the study, and data analysis and interpretation. Yoichiro Yoshikawa drafted the manuscript and Takako Nagao, Tomoko Matsukawa, Miwako Suzuki, Akemi Sebata, Yuko Maeno, Shiro Ibe, Akiko Fukuda, Dong Wang contributed to writing and reviewing the work.

Funding

In this surveillance the surveillance design, collection, analysis, and interpretation of the data were founded by ViiV Healthcare K.K., Tokyo, Japan, to which all authors belong. ViiV Healthcare K.K. also funded the journal’s rapid service and open-access fees.

Data Availability

The datasets generated during and/or analyzed during the current surveillance are available from the corresponding author upon reasonable request.

Declarations

Conflict of Interest

All authors (Yoichiro Yoshikawa, Takako Nagao, Tomoko Matsukawa, Miwako Suzuki, Akemi Sebata, Yuko Maeno, Shiro Ibe, Akiko Fukuda and Dong Wang) are employees of ViiV Healthcare K.K.

Ethical Approval

This post-marketing surveillance was conducted by CMIC HOLDINGS Co., Ltd. (Tokyo, Japan) on behalf of ViiV Healthcare K.K. in compliance with applicable Japanese regulations, including the Ministerial Ordinance on Good Post-marketing Study Practice (GPSP; MHLW No. 171, December 20, 2004), its subsequent amendments, and related notifications. The study protocol was reviewed and approved by the Pharmaceuticals and Medical Devices Agency, the Japanese regulatory authority, and subsequently approved by the ethics committees of each participating institution. In accordance with GPSP regulations, written informed consent was not required for post-marketing surveillance; however, treating physicians provided participants with explanations regarding HIV treatment drugs, including antiretroviral drugs and other HIV-related medications, and obtained verbal consent prior to participation.

Footnotes

Prior Presentation: The results were presented at the 39th Annual Meeting of the Japanese Society for AIDS Research (O18-1, Kumamoto, Japan; December 5–7, 2025).

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References

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (PDF 304 KB) (303.9KB, pdf)

Data Availability Statement

The datasets generated during and/or analyzed during the current surveillance are available from the corresponding author upon reasonable request.

Articles from Advances in Therapy are provided here courtesy of Springer

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