The patient disposition is shown in Fig. 1. A total of 2424 from 30 Japanese sites participating in this HRD cooperative survey were enrolled in the analysis; the required survey forms were collected from 2293 patients. The safety analysis set comprised of 2292 patients, excluding 1 patient who had no hospital visits after the initial visit. The effectiveness analysis set comprised of 2235 patients, excluding 1 patient who received DTG for off-label use (drug use via unapproved administration route: product use issue in PT) and 56 patients with no available HIV RNA copies/mL or CD4+ cell counts at pre and post DTG treatment.
The patient characteristics is shown in Table 1. Of the 2292 patients in the safety analysis set, 2181 patients (95.16%) were male. The mean age at the initial treatment of DTG was 41.1 years (range 13–83 years); the vast majority (95.42%; 2187 patients) were adult (defined as non-elderly aged between 15 and 64 years). The proportion of patients with comorbidities was 62.48% (1432 patients), with hepatic disorder in 19.59% (449 patients) and renal disorder in 6.98% (160 patient). According to CDC classification at pretreatment, more than half of patients (66.71%, 1529 patients) had mild symptoms (category A); the proportion of patients with severe symptoms (category C) was 23.47% (538 patients). A total of 1542 patients (67.28%) received DTG treatment for more than 730 days. The proportion of patients with no treatment histories of ARV backbone at baseline (hereafter, ART-naïve patients) was 45.38% (1040 patients), and those with treatment histories of ARV backbone at baseline (hereafter, ART-experienced patients) was 53.18% (1219 patients). Disposition of the ARV backbone at baseline used was tenofovir disoproxil fumarate (TDF)+/emtricitabine (FTC) (41.80%; 958 patients), ABC+/3TC (39.35%; 902 patients), and tenofovir alafenamide fumarate (TAF)/FTC (13.70%; 314 patients) (Table 1).
The patient characteristics of the effectiveness analysis set were similar to those of the safety analysis set.
The incidence of ADRs by PT observed in at least 10 patients during this survey is shown in Table 2. The full list of the incidence of ADRs is provided in Table S2 in the supplementary material. Of the 2292 patients in the safety analysis set, a total of 565 patients (24.65%) reported at least one ADR. The most common ADRs by SOC (occurred in at least 2% of patients) were investigations (8.29%; 190 patients) which means laboratory test results, gastrointestinal disorders (4.97%; 114 patients), metabolism and nutrition disorders (3.71%; 85 patients), infections and infestations (3.40%; 78 patients), hepatobiliary disorders (3.23%; 74 patients), skin and subcutaneous tissue disorders (3.05%; 70 patients), psychiatric disorders (2.97%; 68 patients), and nervous system disorders (2.01%; 46 patients). The most common ADRs by PT (occurred in at least 1% of patients) were blood creatinine increased (4.28%; 98 patients), hepatic function abnormal (2.31%; 53 patients), nausea (2.05%; 47 patients), insomnia (1.48%; 34 patients), hypertension (1.18%; 27 patients), headache (1.13%; 26 patients), and hyperuricemia (1.05%; 24 patients).
The incidence of serious ADRs is provided in Table S3 in the supplementary material. A total of 147 patients (6.41%) reported at least one serious ADR. The most common serious ADR was immune reconstitution inflammatory syndrome (0.83%; 19 patients), followed by renal impairment (0.74%; 17 patients). Other serious ADRs were reported in fewer than 10 patients. The outcomes of these serious ADRs were death in 7 patients (completed suicide in 2 patients and death, lung adenocarcinoma, lymphoma, myocardial infarction, and near drowning in 1 patient each), not resolved in 53 patients, and unknown in 4 patients; the remaining serious ADRs were recovered or resolving.
ADRs by Patient Characteristics
The incidence of ADRs by patient characteristics is shown in Table 3. There was a statistically significant difference in the incidence of ADRs by CDC classification at pretreatment, presence or absence of comorbidities, liver disorder, renal disorder, and prescription history of ARV backbone. There were no statistically significant differences in age and sex.
For CDC classification at pretreatment, the incidence of ADRs in patients with categories B (46.40% [odds ratio 3.05; 95% CI 2.10–4.42]) and C (28.07% [odds ratio 1.37; 95% CI 1.10–1.72]) was statistically significantly higher than that with category A (22.11%) (p < 0.001). For comorbidities, the incidences of ADRs in patients with comorbidities (31.35% [odds ratio 3.01; 95% CI 2.37–3.82), hepatic disorder (34.74% [odds ratio 1.95; 95%CI 1.56–2.45]), and renal disorder (35.00% [odds ratio 1.66; 95% CI 1.18–2.33]) were statistically significantly higher than those without comorbidities (13.18%; p < 0.001), hepatic disorder (21.43%; p < 0.001), and renal disorder (24.53%; p = 0.004). Whereas the incidence of ADRs was statistically significantly lower in ART-experienced patients (19.93% [odds ratio 0.56; 95% CI 0.46–0.68]) than that in ART-naïve patients (30.77%) (p < 0.001).
The incidence of neuropsychiatric ADRs is shown in Table 4. A total of 107 patients (4.67%) reported at least one neuropsychiatric ADR. The incidence of neuropsychiatric ADRs by SOC was 2.97% for psychiatric disorders (68 patients) and 2.01% for nervous system disorder (46 patients). The most common neuropsychiatric ADR by PT in each SOC was insomnia (1.48%; 34 patients) and headache (1.13%; 26 patients).
The incidence of ADRs related to depression, suicide, or self-injurious behavour is shown by presence or absence of psychiatric disorders comorbidities in Table 5. The incidence of ADRs related to depression was higher in patients with comorbidities of psychiatric disorders than that without those comorbidities (1.12% vs 0.51%); however, the difference was not statistically significant. Whereas the incidence of ADRs related to suicide or self-injurious behavour was statistically significantly higher in patients with comorbidities of psychiatric disorders (1.12% vs 0.05%; p = 0.006).
Time to Onset of ADRs After DTG Treatment
The times to onset of events after treatment with DTG for the ADR groups (at least 10 patients) and ADR groups by company’s interest (suicide- and hepatitis-related) are shown in Table 6. In more than half of the ADR groups (12 of 22 groups), the events occurred within 180 days (median time to ADR onset) after the start of DTG treatment. Of these, the events contained in the following five ADR groups occurred as early as within 30 days (median time to ADR onset): nausea and vomiting (2.0 days), malaise (9.0 days), headache-related (10.0 days), diarrhea (20.0 days), and immune reconstitution inflammatory syndrome-related (22.0 days). Whereas the events contained in the following four ADR groups occurred late (occurred 365 days after the start of DTG treatment): hepatitis-related (370.0 days), blood cholesterol-related (547.5 days), blood pressure-related (568.0 days), and hyperlipidemia-related (790.0 days).
Changes in Body Weight
Shifts in body weight in ART-naïve and ART-experienced patients for 66 months after the start of DTG treatment are shown in Fig. 2, those for 72 months are provided in Fig. S1 in the supplementary material. Shifts in body weight by backbone (ABC+/3TC, TAF/FTC, and TDF+/FTC) for 24 months (ART-naïve patients) and 36 months (ART-experienced patients) after the start of DTG treatment are shown in Fig. 3, those for 72 months are provided in Fig. S2 in the supplementary material.
In these analyses, the evaluated duration was up to the time when 10 or more patients had available body weight in both ART-naïve and ART-experienced patients. A total of 825 patients with available baseline body weight were evaluated among 2292 patients in the safety analysis set.
Body weights (mean ± standard deviation [SD]) in ART-naïve and ART-experienced patients were 66.60 ± 13.52 kg (393 patients) and 68.32 ± 13.36 kg (432 patients) at baseline, and 70.44 ± 7.17 kg (11 patients) and 74.69 ± 13.24 kg (55 patients) at 66 months after the start of DTG treatment (Fig. 2a). The changes in body weight at 66 months after the start of DTG treatment from baseline in ART-naïve and ART-experienced patients were 8.93 ± 8.80 kg and 3.61 ± 4.92 kg (Fig. 2b); the percentage changes were 16.26% ± 16.12% and 5.38% ± 7.32% (Fig. 2c).
In ART-naïve patients, body weights by backbone (ABC+/3TC, TAF/FTC, and TDF+/FTC, the same order hereafter) were 67.15 ± 12.95 kg (163 patients), 67.85 ± 13.44 kg (64 patients), and 66.07 ± 13.53 kg (128 patients) at baseline; 70.84 ± 12.79 kg (77 patients), 72.41 ± 11.54 kg (23 patients), and 68.69 ± 11.92 kg (28 patients) at 24 months after the start of DTG treatment (Fig. 3a). The changes in body weight at 24 months after the start of DTG treatment from baseline were 3.62 ± 6.85 kg, 4.82 ± 8.62 kg, and 4.00 ± 6.16 kg (Fig. 3b); the percentage changes were 5.61% ± 10.17%, 7.92% ± 14.45%, and 6.20% ± 9.32% (Fig. 3c).
In ART-experienced patients, body weights by backbone were 68.48 ± 12.60 kg (250 patients), 70.02 ± 13.51 kg (391 patients), and 68.87 ± 13.71 kg (240 patients) at baseline; 71.50 ± 11.20 kg (70 patients), 74.97 ± 17.09 kg (77 patients), and 73.28 ± 10.78 kg (11 patients) at 36 months after the start of DTG treatment (Fig. 3d). The changes in body weight at 36 months after the start of DTG treatment from baseline were 1.59 ± 4.84 kg, 4.08 ± 5.69 kg, and − 1.55 ± 7.79 kg (Fig. 3e); the percentage changes were 2.71% ± 7.31%, 5.79% ± 7.72%, and − 1.09% ± 9.72% (Fig. 3f).
Shifts in HIV RNA copies/mL and CD4+ cell counts in ART-naïve and ART-experienced patients are shown in Figs. 4 and 5. In these analyses, the patients treated with DTG for at least 60 days and available HIV RNA copies/mL and CD4+ cell counts at pre and post DTG treatment were evaluated among 2235 patients in the effectiveness analysis set. The analysis included 812 ART-naïve patients and 932 ART-experienced patients for HIV RNA copies/mL, and 811 ART-naïve patients and 930 ART-experienced patients for CD4+ cell counts. In ART-naïve patients, HIV RNA copies/mL decreased at 3 months after the start of DTG treatment and remained up to 72 months; CD4+ cell counts increased after the start of DTG treatment. In ART-experienced patients, HIV RNA copies/mL and CD4+ cell counts remained almost unchanged from baseline to 72 months after the start of DTG treatment.