In this study, no CVF was observed and most patients maintained viral suppression. In the ATLAS trial, a phase 3 study, patients who switched to monthly CAB + RPV injections showed similar efficacy and safety at 48 weeks as those who continued their current treatments after initially achieving virological suppression with conventional ART [1]. The ATLAS-2M trial, a phase 3b clinical trial comparing the efficacy and safety of the CAB + RPV bimonthly injection switch group with the CAB + RPV monthly injection switch group, also showed equivalent efficacy and safety at 48 weeks [2]. In the FLAIR trial, another phase 3 trial, patients who began with DTG/abacavir (ABC)/3TC and then switched to monthly CAB + RPV injections were compared with those who continued DTG/ABC/3TC. Both the groups demonstrated similar efficacy and safety at 96 weeks [3].
A combined analysis of the ATLAS, ATLAS-2M, and FLAIR trials examining factors related to CVF 48 weeks after initiating long-acting ART found that among 1,039 participants, 13 (1.3%) experienced CVF [12]. No single factor predicted CVF, but a combination of two or more factors—pro-virus RPV resistance-related mutations, HIV-1 subtype A6/A1, and BMI ≥ 30 kg/m²—resulted in a CVF rate of 25.7%. Although it is difficult to measure pro-virus resistance mutations and HIV-1 subtypes in clinical practice, E138A/G/K RPV resistance-related mutations were found in 8 of 1107 (0.72%) untreated Japanese PLWH [13]. The frequency of HIV-1 subtype A in the Japanese population is 15 of 3838 cases (0.4%) [14], and both E138A/G/K RPV resistance-related mutations and HIV-1 subtype A are relatively rare. The proportion of patients with a BMI ≥ 30 kg/m² among Japanese PLWH who started a tenofovir-containing regimen between 2002 and 2009 was reported as 8 of 494 cases (1.6%) [15]. However, recent reports indicate a link between ART and weight gain in PLWH, with significant weight gain observed after ART initiation compared with non-infected individuals [16], particularly among patients treated with integrase inhibitors and TAF/FTC [16, 17]. A Swiss cohort study observed a rise in obesity among PLWH, with those having a BMI ≥ 30 kg/m² increasing from 4% in 2002 to 9% in 2012 and 12% in 2017 [18]. In our previous study of 543 treated PLWH, in which we used a body composition meter to assess the effect of ART, 218 patients (40.1%) were classified as obese (BMI ≥ 25 kg/m² and body fat percentage ≥ 20%), and 64 patients (11.8%) had a BMI ≥ 30 kg/m² [19]. Thus, obesity in PLWH is an important issue, and the proportion of obese patients with a BMI ≥ 30 kg/m² is expected to increase in Japan. In our study, five patients (13%) had a BMI ≥ 30 kg/m². Two patients switched from long-acting ART back to conventional ART due to HBV reactivation, but the remaining three continued treatment with long-acting ART without developing CVF. Further research is required to determine whether obesity is associated with CVF.
A 2019 study of 2,389 HIV-positive adults from 25 countries, including 75 from Japan, assessed the factors affecting satisfaction with ART [20]. The study found that 36% of the Japanese participants viewed daily ART as a burden, 43% were reminded of their HIV status through daily intake, and 45% felt stressed by daily oral medication. Only 53% of Japanese participants reported no issues in managing their medications daily. The most sought-after improvements in HIV treatment were “reducing side effects” (53%), “minimizing long-term health impact” (48%), and “availability of long-acting treatments not requiring daily intake” (39%). This implies that a notable number of HIV-positive individuals are somewhat dissatisfied with their daily ART intake. In our hospital survey of PLWH [21], 16.2% were dissatisfied with conventional ART, while 54.9% preferred switching to long-acting ART. Although not all who wished to switch could do so, this indicates considerable interest among Japanese PLWH in long-acting ART. In this study, satisfaction with long-acting ART, as evaluated using the HIVTSQs/c, significantly increased. Adherence was high, with 96% of the injections administered on schedule. This suggests that long-acting ART may greatly enhance patient satisfaction, medication adherence, and overall quality of life.
In this study, an improvement in Cre levels was observed after switching to a long-acting ART. Drugs such as cobi, ritonavir (rtv), RPV, DTG, and BIC inhibit transporters, leading to decreased creatinine secretion from the renal tubules. Thus, an initial increase in serum creatinine and a decrease in creatinine clearance is observed. Cobi and DTG do not alter the true glomerular filtration rate [22, 23]. The apparent improvement in renal function due to the decrease in Cre levels can be attributed to the switch from conventional to a long-acting ART. Conversely, TAF, commonly used in conventional ART, is a prodrug of tenofovir disoproxil fumarate (TDF) and is believed to reduce the tubular toxicity associated with TDF [24, 25]. Therefore, TAF is a new treatment option for patients with reduced renal function. However, the US Department of Health and Human Services guidelines [26] recommend careful monitoring when switching from TDF to TAF, owing to the unclear long-term effects on patients with a history of renal disease, including proximal tubular injury, even though the switch is associated with improvements in proteinuria and renal biomarkers. Renal function recovery has been reported in patients with chronic kidney failure who switched to an NRTI-sparing regimen [27, 28]; however, the true improvement in renal function in this study is unclear because of the lack of measurements of urinary markers such as cystatin C and beta-2 microglobulin. Further case accumulation and evaluation of renal function using urinary markers are required to understand the impact of long-acting ART on renal function.
This study has a few limitations. First, it involved a relatively small and homogeneous group of 38 male participants, potentially limiting the generalizability of the findings. A larger and more diverse sample would likely yield more comprehensive insights, applicable to a broader population. Second, being conducted at a single center, the study may reflect particular local practices or patient demographics. Multi-center studies could provide a broader perspective and help reduce the biases associated with single-center research. Third, the absence of a comparative control group in this study design is a notable limitation. Including a control group receiving standard treatment would have enhanced our ability to directly link the observed outcomes to the long-acting therapy. Despite the limitations, the strength of this study is distinguished by its real-world clinical setting, providing practical insights. The extensive data collection over a significant period adds depth to our findings. Importantly, the focus on patient satisfaction introduces a valuable dimension, reflecting a holistic approach to assessing therapy effectiveness.