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Young age is a key determinant of body weight gain after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in Japanese people living with HIV

Open AccessPublished:November 17, 2022DOI:https://doi.org/10.1016/j.jiac.2022.10.014

      Abstract

      Background

      Treatment with tenofovir alafenamide fumarate (TAF) is associated with body weight gain. However, little or no information is available on this issue in Asian populations.

      Methods

      This single-center retrospective study included Japanese people living with HIV (PLWH) who satisfied the following criteria; 1) switching from TDF to TAF after HIV-suppression, 2) follow-up for ≥2 years while on TDF and TAF, and 3) no switching of the third antiretroviral agent. Changes in annual body weight and lipid profiles were compared between the TDF and TAF periods.

      Results

      Of 328 patients, dolutegravir (DTG) was used in 118 PLWH. Overall, no significant difference in weight gain was observed between TDF and TAF (0.76 vs. 0.9 kg/year, p = 0.331). In TAF-period, younger (<50 years of age) group showed significantly greater weight gain than older group (1.03 vs. 0.12 kg/year, p = 0.037). In DTG group, weight gain was larger in TAF-period (0.74 vs. 1.31 kg/year, p = 0.046), especially in younger subgroup (1.43 kg/year) compared with older one (−0.12 kg/year). Multivariate regression analysis showed that TAF was not associated with weight gain (estimates 0.201, p = 0.170) except for DTG group, whereas young age was associated with weight gain in all subjects (estimates −0.033/1 year older, p < 0.001), DTG, RAL, and EFV groups.

      Conclusion

      In Japanese PLWH, annual body weight change was comparable in TDF- and TAF-period, while TAF plus DTG correlated with weight gain. Since young age was a key determinant of weight change, careful interpretation is needed for TAF-associated weight gain.

      Keywords

      1. Introduction

      Tenofovir alafenamide (TAF), the prodrug of tenofovir, is modified to maintain high intracellular tenofovir concentrations despite lower plasma tenofovir concentrations [
      • Markowitz M.
      • Zolopa A.
      • Squires K.
      • Ruane P.
      • Coakley D.
      • Kearney B.
      • et al.
      Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults.
      ], conferring significantly lower nephrotoxicity and bone-toxicity than tenofovir disoproxil fumarates [
      • Gallant J.E.
      • Daar E.S.
      • Raffi F.
      • Brinson C.
      • Ruane P.
      • DeJesus E.
      • et al.
      Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial.
      ,
      • Mills A.
      • Arribas J.R.
      • Andrade-Villanueva J.
      • DiPerri G.
      • Van Lunzen J.
      • Koenig E.
      • et al.
      Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study.
      ,
      • Mayer K.H.
      • Molina J.M.
      • Thompson M.A.
      • Anderson P.L.
      • Mounzer K.C.
      • De Wet J.J.
      • et al.
      Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.
      ]. Recent studies have described the association of TAF with body weight gain [
      • Sax P.E.
      • Erlandson K.M.
      • Lake J.E.
      • McComsey G.A.
      • Orkin C.
      • Esser S.
      • et al.
      Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials.
      ,
      • Venter W.D.F.
      • Moorhouse M.
      • Sokhela S.
      • Fairlie L.
      • Mashabane N.
      • Masenya M.
      • et al.
      Dolutegravir plus two different prodrugs of tenofovir to treat HIV.
      ]. Especially, the combination of TAF and integrase strand transfer inhibitors (INSTIs) has been reported to be associated with increase in body weight both in treatment-naïve patients [
      • Sax P.E.
      • Erlandson K.M.
      • Lake J.E.
      • McComsey G.A.
      • Orkin C.
      • Esser S.
      • et al.
      Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials.
      ,
      • Venter W.D.F.
      • Sokhela S.
      • Simmons B.
      • Moorhouse M.
      • Fairlie L.
      • Mashabane N.
      • et al.
      Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial.
      ] and treatment-experienced patients [
      • Surial B.
      • Mugglin C.
      • Calmy A.
      • Cavassini M.
      • Günthard H.F.
      • Stöckle M.
      • et al.
      Weight and metabolic changes after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV : a cohort study.
      ,
      • Eckard A.R.
      • McComsey G.A.
      Weight gain and integrase inhibitors.
      ]. This effect is of concern especially in Asians, since unlike Caucasians or African Americans, slight weight gain in Asians can be an important predisposing factor for type 2 diabetes mellitus [
      • Chiu M.
      • Austin P.C.
      • Manuel D.G.
      • Shah B.R.
      • Tu J.V.
      Deriving ethnic-specific BMI cutoff points for assessing diabetes risk.
      ]. Furthermore, weight gain is often parallel to lipid elevation, which raise the risk of cardiovascular diseases as in Framingham or Suita score [
      • Nishimura K.
      • Okamura T.
      • Watanabe M.
      • Nakai M.
      • Takegami M.
      • Higashiyama A.
      • et al.
      Predicting coronary heart disease using risk factor categories for a Japanese urban population, and comparison with the framingham risk score: the suita study.
      ]. However, this parallel relationship can be often altered in HIV infection by immune reconstitution, inflammation, and antiretroviral agents. To evaluate the impact of TAF-associated weight gain to cardiovascular diseases, lipid change should be independently evaluated together.
      To date, several issues remain unsolved regarding TAF-related body weight gain. First, the majority of currently available data on TAF-related body weight gain was generated from studies on Caucasian or African American populations [
      • Sax P.E.
      • Erlandson K.M.
      • Lake J.E.
      • McComsey G.A.
      • Orkin C.
      • Esser S.
      • et al.
      Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials.
      ], with only a few data on Asian populations, who generally have smaller body size and lower body mass index (BMI) [
      • Ando N.
      • Nishijima T.
      • Mizushima D.
      • Inaba Y.
      • Kawasaki Y.
      • Kikuchi Y.
      • et al.
      Long-term weight gain after initiating combination antiretroviral therapy in treatment-naïve Asian people living with human immunodeficiency virus.
      ,
      • Kanda N.
      • Okamoto K.
      • Okumura H.
      • Mieno M.
      • Sakashita K.
      • Sasahara T.
      • et al.
      Outcomes associated with treatment change from tenofovir disoproxil fumarate to tenofovir alafenamide in HIV-1-infected patients: a real-world study in Japan.
      ]. Second, studies conducted in treatment-naïve patients showed that the body weight gain was largely affected by the immune reconstitution, which can cause overestimation of TAF-associated body weight gain. To adjust for immune reconstitution, studies need to be conducted in treatment-experienced patients who switch TDF to TAF after sustained viral suppression. Third, the impact of a third agent of antiretroviral therapy (ART) on body weight gain should be adjusted appropriately. Especially, protease inhibitors were reported to cause various metabolic disorders [
      • Bernasconi E.
      Metabolic effects of protease inhibitor therapy.
      ], and the second generation INSTIs are also known to cause body weight gain [
      • Sax P.E.
      • Erlandson K.M.
      • Lake J.E.
      • McComsey G.A.
      • Orkin C.
      • Esser S.
      • et al.
      Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials.
      ]. Thus, there is a need for separate evaluation of TAF-associated weight gain for each third ART agent.
      We designed the present third agent-based cohort study to evaluate TAF-associated body weight gain and lipid elevation in treatment-experienced HIV-infected Japanese individuals who switched TDF to TAF after sustained viral suppression.

      2. Materials and methods

      2.1 Sample populations and data collection

      This retrospective single-center study was conducted at Tokyo Medical University Hospital on Japanese people living with HIV (PLWH) who satisfied the following inclusion criteria; 1) switched from TDF to TAF after at least two consecutive HIV-RNA levels <50 copies/mL following TDF-containing therapy, 2) followed-up for ≥2 years each of both TDF- and TAF-period, 3) received dolutegravir (DTG), raltegravir (RAL), darunavir (DRV), or efavirenz (EFV) as the third ART agent, and 4) did not switch to a different third ART agent during the study period. The following exclusion criteria were also applied; 1) treatment-naïve PLWH, 2) PLWH treated with dual antiretroviral agents, 3) PLWH with history of interruption of ART, 4) PLWH with malignancy, and 5) PLWH who were on continuous use of steroids (Fig. 1).
      Fig. 1
      Fig. 1Enrollment flow of study populations. PLWH: people living with HIV, TDF; tenofovir disoproxil fumarate, TAF; tenofovir alafenamide, ABC; abacavir, DTG; dolutegravir, RAL; raltegravir, DRV; darunavir, EFV; efavirenz.
      The clinical characteristics, body weight, and laboratory tests values recorded during the period of January 2015 to March 2020 were obtained from the medical records. For treatment, the switch day was defined as month 0. The values of body weight, body mass index (BMI) and lipid profile [total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and TC/HDL-C ratio] were collected from 24 months before (month −24) to 24 months after (month 24) the switch. Consecutive data of the above parameters were obtained every 12 months (months −24, −12, 0, 12, and 24).
      The present study was approved by the Ethics Review Committee of Tokyo Medical University (#SH3751) and was conducted according to the principles of the Declaration of Helsinki.

      2.2 Statistical analysis

      Data are reported as mean ± SEM. The demographic characteristics of the participating patients were compared by the third antiretroviral groups (DTG, RAL, DRV, and EFV). For comparison among the four types of the third ART agents, one-way analysis of variance (ANOVA) was used for continuous variables, and either the chi-square or Fisher's exact test was conducted for categorical variables. The annual change in body weight (kg/year) was compared between TDF-period and TAF-period by Wilcoxon's signed rank test. BMI was recorded every year and classified into five categories based on the WHO definition of obesity; BMI <18.5 kg/m2 representing “underweight”, ≥18.5 to <25 kg/m2 for “normal range”, ≥25 to <30 kg/m2 for “pre-obese”, ≥30 to <35 kg/m2 for “obese class I″, and ≥35 kg/m2 for “obese class II”. Furthermore, the annual change in body weight gain (kg/year) was compared between the TDF- and TAF-period by the two age groups (<50 vs. ≥50 years of age) by the paired t-test. Next, weight change was compared between two age groups in TDF- and TAF-period respectively, by the unpaired t-test. For more precise evaluation of the relationships between multiple risk factors and annual body weight change, multivariate linear regression models with five variables (TAF, ≥50 years of age, sex, height, and use of lipid-lowering agents) were generated for all populations and for each third ART agents. The total changes in TC, HDL-C, LDL-C, TG, and TC/HDL-C were also compared between TDF- and TAF-period by the paired t-test. Multiple linear regression models were generated to adjust for age, sex, and use of lipid-lowering agents. Statistical significance was defined as two-sided p value of <0.05. All statistical analyses were performed using the Statistical Package for Social Sciences (ver. 23.0, SPSS, Chicago, IL).

      3. Results

      3.1 Patient characteristics

      A total of 328 HIV-infected patients were included in the study (Fig. 1). Of those, 323 (98.4%) were males and the mean age of all participants was 40.9 ± 0.5 years. The mean body weight at baseline was 69.4 ± 0.7 kg, with a mean BMI of 24.0 ± 0.2 kg/m2. With regard to the third ART agents, 118 (35.9%) patients received DTG, 135 (41.2%) received RAL, 50 (14.0%) received DRV, and 25 (7.6%) patients received EFV. Among the third agent groups, DTG and DRV groups included relatively younger population (mean age, 39.7 and 39.4 years, respectively) compared with the RAL and EFV groups (42.1 and 43.9 years, respectively, Table 1, p = 0.037). There were no significant differences among the third agent groups in sex, body weight, BMI, CD4 cell count, undetectable HIV-RNA, smoking status, and use of anti-lipid agents (Table 1).
      Table 1Patients characteristics.
      ALLDTG groupRAL groupDRV groupEFV groupp-value
      n (%)328118 (36.0)135 (41.2)50 (15.2)25 (7.6)
      Age, mean ± SEM, (years)40.9 ± 0.539.7 ± 7.542.1 ± 10.139.4 ± 7.443.9 ± 7.50.037
      >50 years, n (%)43 (13.1)9 (7.6)24 (17.8)5 (10)5 (20)
      Sex, Male (%)323 (98.4)117 (99.2)133 (98.5)50 (100)24 (96)0.489
      Weight, mean ± SEM (kg)69.4 ± 0.769.1 ± 12.769.4 ± 11.569.6 ± 11.271.3 ± 9.60.861
      BMI, mean ± SEM (kg/m2)24.0 ± 0.223.5 ± 3.724.4 ± 4.023.9 ± 3.924.3 ± 3.20.386
       <18.59 (2.7)8 (6.8)3 (2.2)2 (4)0 (0)
       ≥18.5 to <25.0185 (56.4)74 (62.7)80 (59.3)31 (62)14 (56)
       ≥25.0 to <30.0103 (31.4)30 (25.4)43 (36.4)13 (26)10 (40)
       ≥30.031 (9.5)6 (5.1)9 (6.67)4 (8)4 (16)
      Baseline CD4 cell count, mean ± SEM (/μL)686 ± 270677 ± 238699 ± 295692 ± 267655 ± 2710.858
      Smoking
       Never125 (38.1)48 (49.8)57 (42.2)16 (32.0)4 (16.0)0.213
       Past100 (30.5)31 (26.2)42 (31.1)13 (26.0)14 (56.0)0.213
       Current103 (31.4)39 (33.0)36 (26.7)21 (42.0)7 (28.0)0.213
      Use of lipid-lowering agents21 (6.4)5 (4.2)11 (8.1)3 (6)2 (8)0.582
      DTG; dolutegravir, RAL; raltegravir, DRV; darunavir, EFV; efavirenz, SEM; standard error of mean, BMI; body mass index.

      3.2 Weight change in TDF vs. TAF-period

      Fig. 2 demonstrates the weight change before and after the switch from TDF to TAF, which were each used for 2 years. Irrespective of TDF- and TAF-period, body weight progressively increased during the study period; analysis of the entire group showed no significant difference in weight change between the TDF- and TAF-period (0.76 vs. 0.91 kg/year, p = 0.331) (Fig. 2A). However, in the DTG group, body weight gain was significantly larger in the TAF-period than in TDF-period (1.30 vs. 0.74 kg/year, p = 0.046) (Fig. 2B). For the TAF-period, a larger body weight gain was recorded in the first year of TAF-period in the all-sample population (1.32 kg/year in the first year of TAF-period vs. 0.50 kg/year in the second year, p = 0.009) (Fig. 2A), and in the DTG group, the largest weight gain was observed in the first year of TAF-period (1.89 kg/year in the first year vs. 0.68 kg/year in the second year, p = 0.024) (Fig. 2B). In contrast, in the groups other than DTG (RAL, DRV, and EFV), there was no significant difference in the annual weight gain between the TDF and TAF periods. (Fig. 2C–E). In the second year of TAF-period, the annual body weight change was comparable to the first and second year of TDF-period in all groups.
      Fig. 2
      Fig. 2Body weight changes in TDF- and TAF-period associated with various third ART agents. Analysis of data of the entire group showed no difference in weight change between TDF- and TAF-period (0.76 vs. 0.91 kg/year, p = 0.331). A larger body weight gain was noted in the TAF-period (0.74 vs. 1.30 kg/year, p = 0.003) in subjects treated with DTG, especially in the first year of TAF-period (1.89 kg/year). Bars represent standard error of mean.

      3.3 BMI changes in TDF-and TAF-period

      Fig. 3 demonstrates the change in five BMI categories during the study period. For the entire study population, the proportion of patients with BMI ≥25 kg/m2 increased from 35.9% at baseline to 47.4% at the end of the observation period, and the change in the prevalence was comparable between the TDF- and TAF-period (4.9% vs. 6.7% respectively). On the other hand, for the DTG group, the change in the prevalence of BMI ≥25 kg/m2 was larger in the TAF-period than in TDF-period (4.2% in the TAF-period vs. 12.6% in the TDF-period).
      Fig. 3
      Fig. 3Annual BMI changes in TDF- and TAF-period in patients treated with various third ART agents. Analysis of data of the entire group showed persistent increase in overweight population (BMI ≥25 kg/m2) in both the TDF- and TAF-period (+4.9% increase in TDF-period and +6.6% in TAF-period).

      3.4 Effect of age on weight change in TDF- and TAF-period

      Next, we examined the effect of age on the annual weight change in the TDF- and TAF-periods (Fig. 4), by comparing the results of the younger group (<50 years, n = 285) and the older group (≥50 years, n = 43). For the entire group, no difference was found between TDF and TAF period in younger or older group (0.78 kg/year in TDF-period vs. 1.03 kg/year in TAF-period in <50 group, p = 0.161, and 0.57 kg/year in TDF-period vs. 0.12 kg/year in TAF-period in the ≥50 group, p = 0.175). However, in TAF period, older group showed significantly smaller weight change than younger group (0.12 kg/year in older group vs. 1.03 kg/year in younger group, p = 0.037). A similar analysis was conducted to examine the effect of type of the third ART. In the DTG group, the annual weight gain was larger in the TAF-period than in TDF-period in the <50 group (0.68 kg/year in TDF-period vs. 1.43 kg/year in TAF-period, p = 0.012), whereas no significant difference in the annual weight change was observed in the ≥50 group (1.37 kg/year in TDF-period vs. −0.12 kg/year in TAF-period, p = 0.172). Moreover, in TAF period, older group showed significantly smaller weight change than younger group (−0.12 kg/year in older group vs. 1.43 kg/year in younger group, p = 0.037).
      Fig. 4
      Fig. 4Annual body weight changes in TDF- and TAF-period by age for each of the third ART agent. Analysis of data of the entire group showed that although not significant by the paired t-test, younger Japanese PLWH tended to show larger body weight gain in TAF-period, compared with their older counterparts. The addition of DTG resulted in a significantly larger body weight gain in younger PLWH in the TAF-period (0.68 kg/year in TDF-period vs. 1.43 kg/year in TAF-period, p = 0.012), compared with their older counterparts (1.37 kg/year in TDF-period vs. −0.12 kg/year in TAF-period, p = 0.172). Boxes represent interquartile ranges and whiskers represent 95% confidence intervals.

      3.5 Changes in lipid profiles in TDF- and TAF-period

      We also examined the changes in lipid profile in TDF-and TAF-period (Fig. 5). Analysis of data of the whole group showed larger increases in TC, HDL-C, LDL-C, and TG in TAF- than TDF-based treatment. Specifically, the increases in TC and LDL-C were larger in the TAF-period regardless of the type of the third ART agent (TC increased 6.9 mg/dL in TDF-period and 22.1 mg/dL in TAF-period. LDL-C increased 6.4 mg/dL in TDF-period and 15.6 mg/dL in TAF-period, p < 0.001). In contrast, no such differences were noted in the TC/HDL-C ratio in both periods (0.11 in TDF-period vs. 0.12 in TAF-period). In the DTG group, the increases in TC and LDL-C were larger in the TAF-period, while TC/HDL-C was comparable between the TDF- and TAF-period (0.17 in TDF-period vs. 0.04 in TAF-period).
      Fig. 5
      Fig. 5Lipid profile changes in the TDF- and TAF-periods induced by treatment with the third ART agents. Total cholesterol (TC) and LDL-C increased significantly in the TAF-period in all third agent groups, whereas the change in TC/HDL-C ratio was comparable between the TDF- and TAF-period in all third ART agents. Boxes represent interquartile ranges and whiskers represent 95% confidence intervals.

      3.6 Multivariate linear regression analysis for body weight gain and lipid profiles

      Table 2A shows the results of multiple regression analysis according to the type of the third ART agent after adjustment for the effects of various confounding factors on body weight change, including age, sex, height, use of lipid-lowering agent, and TAF. Analysis of data of the entire study patients showed that TAF use was not associated with significant body weight gain [estimate 0.201, 95% confidence interval (95%CI) (−0.086 to 0.489), p = 0.170]. In the DTG group, TAF treatment was associated with larger body weight gain (estimate 0.627, 95%CI 0.103 to 1.151, p = 0.019).
      Table 2AResults of multiple linear regression analyses for weight gain by third ART agents.
      ALLDTGRALDRVEFV
      estimatep-value95% CIestimatep-value95% CIestimatep-value95% CIestimatep-value95% CIestimatep-value95% CI
      Age (per 1 year older)−0.033<0.001−0.049 to −0.016−0.0530.003−0.087 to −0.018−0.0240.042−0.046 to 0.001−0.020.390−0.065 to 0.025−0.0670.043−0.132 to −0.002
      Sex (male = 0, female = 1)−0.8890.188−2.212 to,0.435−1.1330.446−4.058 to 1.792−0.1030.916−2.023 to 1.817NANANA−2.6380.041−5.169 to −0.107
      Height (per 1 cm increase)0.0240.063−0.001 to 0.0480.0090.689−0.036 to 0.0550.0190.331−0.019 to 0.0570.1030.0020.038 to 0.1680.0020.974−0.104 to 0.107
      TAF0.2010.17−0.086 to 0.4890.6270.0190.103 to 1.1510.0070.977−0.433 to 0.446−0.1140.737−0.784 to 0.557−0.0080.985−0.893 to 0.877
      use of lipid-lowering agents0.2320.437−0.353 to 0.8160.420.512−0.840 to 1.6790.3080.478−0.547 to 1.164−0.1580.799−1.384 to 1.068−0.0370.967−1.821 to 1.746
      DTG; dolutegravir, RAL; raltegravir, DRV; darunavir, EFV; efavirenz, TAF; tenofovir alafenamide, 95%CI; 95% confidence interval.
      Of note, younger age was associated with significantly larger body weight gain (estimate −0.033 for 1 year older, 95%CI -0.049 to −0.016, p = 0.006). Remarkably, younger age was also associated with larger weight gain in the majority of the third ART agents (estimate −0.053, −0.024, and −0.067 for the DTG, RAL, and EFV groups, respectively). In contrast, TAF was associated with increases in absolute levels of TC, LDL-C, HDL-C, and TG, independent to age, sex, or use of lipid-lowering agents, whereas age was not associated with an increase in lipid profile. However, the TC/HDL-C ratio did not correlate with TAF-use [Table 2B] .
      Table 2BResults of multiple linear regression analyses of data of all study patients for lipid profile changes.
      TCLDL-CHDL-CTGTC/HDL-C ratio
      estimatep-value95% CIestimatep-value95% CIestimatep-value95% CIestimatep-value95% CIestimatep-value95% CI
      Age (per 1 year older)−0.1120.336−0.34 to 0.1160.0050.969−0.236 to −0.245−0.0310.422−0.108 to 0.0450.0620.918−1.11 to 1.234−0.0030.474−0.013 to 0.006
      Sex (male = 0, female = 1)−13.7380.136−31.807 to,4.331−3.4810.720−22.511 to 15.5501.2950.418−4.792 to 7.381−42.3390.370−135.105 to 50.426−0.4890.187−1.216 to 0.238
      TAF15.326<0.00111.373 to 19.2799.265<0.0015.102 to 13.4283.250<0.0011.918 to 4.58239.933<0.00119.639 to 60.2770.0150.229−0.150 to 0.628
      use of lipid lowering agents3.0170.317−2.898 to 8.9331.0910.731−5.139 to 7.3210.0110.991−1.982 to 2.0040.8300.957−29.539 to 31.1990.0900.459−0.148 to 0.328
      TC: total cholesterol, LDL-C; low-density lipoprotein cholesterol, HDL-C; high-density lipoprotein cholesterol, TG; triglycerides, 95%CI; 95% confidence interval.

      4. Discussion

      The present study enrolled the sample population with 1) sustained HIV suppression, 2) maintained treatment with third ART agents, 3) more than 2 years data of each of TDF- and TAF-period. The majority of previous studies on Asian people with HIV did not satisfy the above criteria or adjust for confounding factors (especially age) on weight gain [
      • Ando N.
      • Nishijima T.
      • Mizushima D.
      • Inaba Y.
      • Kawasaki Y.
      • Kikuchi Y.
      • et al.
      Long-term weight gain after initiating combination antiretroviral therapy in treatment-naïve Asian people living with human immunodeficiency virus.
      ,
      • Kanda N.
      • Okamoto K.
      • Okumura H.
      • Mieno M.
      • Sakashita K.
      • Sasahara T.
      • et al.
      Outcomes associated with treatment change from tenofovir disoproxil fumarate to tenofovir alafenamide in HIV-1-infected patients: a real-world study in Japan.
      ,
      • Kuo P.H.
      • Sun H.Y.
      • Chuang Y.C.
      • Wu P.Y.
      • Liu W.C.
      • Hung C.C.
      Weight gain and dyslipidemia among virally suppressed HIV-positive patients switching to co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.
      ]. Our results showed that switching to TAF was not associated with significantly greater weight gain than the TDF-period in Japanese patients treated with any of the third agents. Specifically, TAF-associated weight gain was limited to the first year after the switch, a finding consistent with that of previous large US and European cohort studies [
      • Surial B.
      • Mugglin C.
      • Calmy A.
      • Cavassini M.
      • Günthard H.F.
      • Stöckle M.
      • et al.
      Weight and metabolic changes after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV : a cohort study.
      ,
      • Mallon P.W.
      • Brunet L.
      • Hsu R.K.
      • Fusco J.S.
      • Mounzer K.C.
      • Prajapati G.
      • et al.
      Weight gain before and after switch from TDF to TAF in a U.S. cohort study.
      ].
      However, this finding does not directly indicate the safety of TAF with regard to metabolic disorders. In the Asian population, even a small body weight gain increases the risk of metabolic disorders [
      • Chiu M.
      • Austin P.C.
      • Manuel D.G.
      • Shah B.R.
      • Tu J.V.
      Deriving ethnic-specific BMI cutoff points for assessing diabetes risk.
      ,
      • Caleyachetty R.
      • Barber T.M.
      • Mohammed N.I.
      • Cappuccio F.P.
      • Hardy R.
      • Mathur R.
      • et al.
      Ethnicity-specific BMI cutoffs for obesity based on type 2 diabetes risk in England: a population-based cohort study.
      ]. Since the annual weight gain of >0.5 kg/year in general Japanese males of middle-to-late adulthood was observed only in 20% [
      • Nanri A.
      • Mizoue T.
      • Takahashi Y.
      • Matsushita Y.
      • Noda M.
      • Inoue M.
      • et al.
      Association of weight change in different periods of adulthood with risk of type 2 diabetes in Japanese men and women: the Japan Public Health Center-Based Prospective Study.
      ,
      • Sogabe N.
      • Sawada S.S.
      • Lee I.M.
      • Kawakami R.
      • Ishikawa-Takata K.
      • Nakata Y.
      • et al.
      Weight change after 20 years of age and the incidence of dyslipidemia: a cohort study of Japanese male workers.
      ]; our results suggest that the weight gain in our Japanese PLWH was larger than the general population, irrespective of class of the ART. For a better understanding of the association between HIV treatment and weight gain, further studies are needed to determine the clinical importance of inflammation-related metabolic disorders, instead of simple comparison of weight gain between ARTs.
      The important finding of our study is that younger age was associated with significant weight gain in Japanese PLWH treated with third ART agents, while such effect was only noticed with DTG in the TAF-period. Our group data analysis showed weight gain only in the <50 PLWH age group during the TAF-period (1.1 kg/year) but not in the ≥50 year group (0.18 kg/year). Furthermore, this age-specific weight change pattern was even more pronounced when TAF was combined with DTG in the ≤50 group (1.42 kg/year), compared with −0.15 kg/year in the ≥50 group. These findings are consistent with the results of a large Italian cohort, where elderly PLWH (>65 years) did not show significant weight gain after the switch to DTG [
      • Guaraldi G.
      • Calza S.
      • Milic J.
      • Calcagno A.
      • Focà E.
      • Rota M.
      • et al.
      Dolutegravir is not associated with weight gain in antiretroviral therapy experienced geriatric patients living with HIV.
      ]. The AGEhIV cohort also reported that excessive weight gain rarely occurred after switching to INSTI in the elderly [
      • Verboeket S.O.
      • Boyd A.
      • Wit F.W.
      • Verheij E.
      • Schim van der Loeff M.F.
      • Kootstra N.
      • et al.
      Generally rare but occasionally severe weight gain after switching to an integrase inhibitor in virally suppressed AGEhIV cohort participants.
      ]. Although RAL has been proved to be the most lipid-favorable agent in a number of randomized clinical trials [
      • Ofotokun I.
      • Na L.H.
      • Landovitz R.J.
      • Ribaudo H.J.
      • McComsey G.A.
      • Godfrey C.
      • et al.
      Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: actg 5257.
      ,
      • Lennox J.L.
      • DeJesus E.
      • Lazzarin A.
      • Pollard R.B.
      • Madruga J.V.
      • Berger D.S.
      • et al.
      Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial.
      ], large real-world analyses in age-unmatched ART groups reported that RAL had a larger effect on weight gain and lipid profiles, compared to other agents [
      • Bansi-Matharu L.
      • Phillips A.
      • Oprea C.
      • Grabmeier-Pfistershammer K.
      • Günthard H.F.
      • De Wit S.
      • et al.
      Contemporary antiretrovirals and body-mass index: a prospective study of the RESPOND cohort consortium.
      ,
      • Rebeiro P.F.
      • Jenkins C.A.
      • Bian A.
      • Lake J.E.
      • Bourgi K.
      • Moore R.D.
      • et al.
      Risk of incident diabetes mellitus, weight gain, and their relationships with integrase inhibitor-based initial antiretroviral therapy among persons with human immunodeficiency virus in the United States and Canada.
      ,
      • Achhra A.C.
      • Mocroft A.
      • Reiss P.
      • Sabin C.
      • Ryom L.
      • de Wit S.
      • et al.
      Short-term weight gain after antiretroviral therapy initiation and subsequent risk of cardiovascular disease and diabetes: the D:A:D study.
      ]. For better interpretation of the association of ART with body weight gain and/or lipid profiles, attention should be paid to age heterogeneity in the study group. The clinical relevance of the association of younger patients with HIV and body weight gain during treatment is not clear. In healthy population, body weight gradually increases up to 60 years of age, and then decreases following fat redistribution into the abdomen and reduction in lean body mass [
      • Borkan G.A.
      • Hults D.E.
      • Gerzof S.G.
      • Robbins A.H.
      Comparison of body composition in middle-aged and elderly males using computed tomography.
      ,
      • Seidell J.C.
      • Visscher T.L.
      Body weight and weight change and their health implications for the elderly.
      ]. Our study showed a closer relationship between age and weight gain during the TAF-period compared to that in healthy population. Weight gain cannot be simply interpreted as drug-specific adverse effect but as consequence of immune reconstitution induced by long-term HIV suppression.
      Our results showed that TAF was an independent factor for increases in plasma levels of TC, LDL-C, and HDL-C, and TG, adding support to the findings of previous studies [
      • Surial B.
      • Mugglin C.
      • Calmy A.
      • Cavassini M.
      • Günthard H.F.
      • Stöckle M.
      • et al.
      Weight and metabolic changes after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV : a cohort study.
      ,
      • Orkin C.
      • DeJesus E.
      • Ramgopal M.
      • Crofoot G.
      • Ruane P.
      • LaMarca A.
      • et al.
      Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.
      ]. However, since the TC/HDL-C ratio did not change following the switch from TDF to TAF, the change in absolute values of lipids in the TAF-period needs careful interpretation. First, since TDF itself has lipid-lowering effect [
      • Santos J.R.
      • Saumoy M.
      • Curran A.
      • Bravo I.
      • Llibre J.M.
      • Navarro J.
      • et al.
      The lipid-lowering effect of tenofovir/emtricitabine: a randomized, crossover, double-blind, placebo-controlled trial.
      ,
      • Valantin M.A.
      • Bittar R.
      • de Truchis P.
      • Bollens D.
      • Slama L.
      • Giral P.
      • et al.
      Switching the nucleoside reverse transcriptase inhibitor backbone to tenofovir disoproxil fumarate + emtricitabine promptly improves triglycerides and low-density lipoprotein cholesterol in dyslipidaemic patients.
      ], lipid elevation after switching TDF to TAF is likely overestimated. Second, irrespective of ART class, most of the ART used in this study have demonstrated persistent and gradual lipid rise even after long-term sustained viral suppression [
      • Saumoy M.
      • Sanchez-Quesada J.L.
      • Ordoñez-Llanos J.
      • Podzamczer D.
      Do all integrase strand transfer inhibitors have the same lipid profile? Review of randomised controlled trials in naïve and switch scenarios in HIV-infected patients.
      ,
      • Patel D.A.
      • Snedecor S.J.
      • Tang W.Y.
      • Sudharshan L.
      • Lim J.W.
      • Cuffe R.
      • et al.
      48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis.
      ]. This therapy-related dyslipidemia cannot be explained reasonably by the drug-specific adverse effect. Third, other studies reported that absolute levels of lipids were less associated with coronary atherosclerosis in HIV-positive than -negative populations, and that TC/HDL-C was the strongest predictor of coronary atherosclerosis [
      • Whelton S.P.
      • Deal J.A.
      • Zikusoka M.
      • Jacobson L.P.
      • Sarkar S.
      • Palella Jr., F.J.
      • et al.
      Associations between lipids and subclinical coronary atherosclerosis.
      ]. One possible explanation is the association between HIV-related inflammation and lipid-profile or fat distribution [
      • Lampe F.C.
      • Duprez D.A.
      • Kuller L.H.
      • Tracy R.
      • Otvos J.
      • Stroes E.
      • et al.
      Changes in lipids and lipoprotein particle concentrations after interruption of antiretroviral therapy.
      ]. A number of randomized studies concluded that body fat distribution during treatment is not determined by the ART class but by pre-treatment viral load [
      • McComsey G.A.
      • Moser C.
      • Currier J.
      • Ribaudo H.J.
      • Paczuski P.
      • Dubé M.P.
      • et al.
      Body composition changes after initiation of raltegravir or protease inhibitors: ACTG A5260s.
      ]. The D.A.D study also showed that the incidence of cerebrovascular disease was associated with lower pre-treatment BMI [
      • Achhra A.C.
      • Mocroft A.
      • Reiss P.
      • Sabin C.
      • Ryom L.
      • de Wit S.
      • et al.
      Short-term weight gain after antiretroviral therapy initiation and subsequent risk of cardiovascular disease and diabetes: the D:A:D study.
      ]. Although the authors speculated that the larger weight change was a risk factor for cerebrovascular disease or metabolic disorders, nowadays it may be more reasonable to suggest that a significant proportion of underweight HIV patients are exposed to HIV-related inflammation, compared with the risk of metabolic disorders. Excessively high levels of several inflammatory cytokines, such as TNFα, IL-1β, and IL-6 are found in patients with HIV [
      • Younas M.
      • Psomas C.
      • Reynes J.
      • Corbeau P.
      Immune activation in the course of HIV-1 infection: causes, phenotypes and persistence under therapy.
      ], and these levels correlate with the size of proviral HIV and residual HIV-RNA [
      • McLaughlin M.M.
      • Ma Y.
      • Scherzer R.
      • Rahalkar S.
      • Martin J.N.
      • Mills C.
      • et al.
      Association of viral persistence and atherosclerosis in adults with treated HIV infection.
      ]. Several important findings were reported on HIV-related inflammation and metabolic disorders by the SMART study: 1) interruption of ART caused not only outgrowth of viral proliferation but also sudden drop in lipid profiles with spikes in various inflammatory markers [
      • Lampe F.C.
      • Duprez D.A.
      • Kuller L.H.
      • Tracy R.
      • Otvos J.
      • Stroes E.
      • et al.
      Changes in lipids and lipoprotein particle concentrations after interruption of antiretroviral therapy.
      ]; 2) the incidence of type 2 diabetes did not correlate with the type of ART but rather with the levels of inflammatory cytokines [
      • Béténé A.D.C.
      • De Wit S.
      • Neuhaus J.
      • Palfreeman A.
      • Pepe R.
      • Pankow J.S.
      • et al.
      Interleukin-6, high sensitivity C-reactive protein, and the development of type 2 diabetes among HIV-positive patients taking antiretroviral therapy.
      ].
      Our study has several limitations. First, the study did not evaluate the change in body weight and lipid profiles immediately after the switch to TDF, hence, the change in the TDF-period can be underestimated. Second, 6.4% of the enrolled patients were on treatment with lipid-lowering agents during the observation period, which could have affected their lipid profiles. Although we adjusted our data for the impact of treatment with lipid-lowering agents on body weight gain, the duration of such treatment was not assessed in our regression models. Third, although HIV-associated chronic inflammation seems to be a key factor for interpretation of TAF-associated body weight gain and lipid profiles, the present study did not evaluate changes in inflammation markers.

      5. Conclusions

      In Japanese PLWH, the combination treatment of TAF and DTG, but not TAF alone, was associated with body weight gain, a finding consistent with the results reported previously in Caucasians. Interestingly, TAF-associated weight gain was limited to <50-year-old PLWH and to the first year after the switch of therapy. The clinical implications of these findings need to be carefully interpreted in the context of both improvement of chronic inflammation as well as drug adverse effects.

      Funding

      This work was not supported by government or private agencies.

      Author contributions

      RS and EK conceived and designed the study. RS, TM, AK, YC, MB, MY, TH, KA, and EK collected the data. RS and EK analyzed the data. EK supervised the study and drafted the main findings. RS wrote the manuscript. All authors critically revised the manuscript for intellectual content and approved the final version submitted for publication.

      Declaration of competing interest

      The authors declare no conflict of interest.

      Acknowledgment

      The authors thank Yoshiko Kamikubo, Tomoko Yamaguchi, Ryui Miyashita, Yuko Harada, and Shun Kaneko for data collection.

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