Switching tenofovir/emtricitabine plus lopinavir/r to raltegravir plus Darunavir/r in patients with suppressed viral load did not result in improvement of renal function but could sustain viral suppression: a randomized multicenter trial

Takeshi Nishijima, Hiroyuki Gatanaga, Takuro Shimbo, Hirokazu Komatsu, Tomoyuki Endo, Masahide Horiba, Michiko Koga, Toshio Naito, Ichiro Itoda, Masanori Tei, Teruhisa Fujii, Kiyonori Takada, Masahiro Yamamoto, Toshikazu Miyakawa, Yoshinari Tanabe, Hiroaki Mitsuya, Shinichi Oka, SPARE study team, Michiyo Ishisaka, Mikiko Ogata, Misao Takano, Akiko Nakano, Masahiro Imamura, Junji Tanaka, Satoshi Hashino, Takeshi Kondo, Mitsufumi Nishio, Katsuya Fujimoto, Hiroshi Moro, Aikichi Iwamoto, Tomohiko Koibuchi, Takeshi Fujii, Toshiyuki Miura, Hitomi Nakamura, Nahoko Miyazaki, Kazufumi Matsumoto, Kumiko Sumino, Noriko Fujiwara, Mizue Saita, Akihito Suzuki, Mika Tanei, Rino Sakamoto, Satoshi Kimura, Kunihiko Okada, Asuka Takasoe, Seiji Saito, Sayaka Sugihara, Fumiko Kagiura, Yuichi Murakami, Rumi Minami, Soichiro Takahama, Junichi Kiyasu, Shuzo Matsushita, Naoki Ishizuka, Yoshimi Kikuchi, Katsuji Teruya, Kunihisa Tsukada, Junko Tanuma, Hirohisa Yazaki, Haruhito Honda, Ei Kinai, Koji Watanabe, Takahiro Aoki, Daisuke Mizushima, Ikumi Genka, Miwako Honda, Masayuki Chida, Junichi Masuda, Mai Nakamura, Fumihide Kanaya, Takeshi Nishijima, Hiroyuki Gatanaga, Takuro Shimbo, Hirokazu Komatsu, Tomoyuki Endo, Masahide Horiba, Michiko Koga, Toshio Naito, Ichiro Itoda, Masanori Tei, Teruhisa Fujii, Kiyonori Takada, Masahiro Yamamoto, Toshikazu Miyakawa, Yoshinari Tanabe, Hiroaki Mitsuya, Shinichi Oka, SPARE study team, Michiyo Ishisaka, Mikiko Ogata, Misao Takano, Akiko Nakano, Masahiro Imamura, Junji Tanaka, Satoshi Hashino, Takeshi Kondo, Mitsufumi Nishio, Katsuya Fujimoto, Hiroshi Moro, Aikichi Iwamoto, Tomohiko Koibuchi, Takeshi Fujii, Toshiyuki Miura, Hitomi Nakamura, Nahoko Miyazaki, Kazufumi Matsumoto, Kumiko Sumino, Noriko Fujiwara, Mizue Saita, Akihito Suzuki, Mika Tanei, Rino Sakamoto, Satoshi Kimura, Kunihiko Okada, Asuka Takasoe, Seiji Saito, Sayaka Sugihara, Fumiko Kagiura, Yuichi Murakami, Rumi Minami, Soichiro Takahama, Junichi Kiyasu, Shuzo Matsushita, Naoki Ishizuka, Yoshimi Kikuchi, Katsuji Teruya, Kunihisa Tsukada, Junko Tanuma, Hirohisa Yazaki, Haruhito Honda, Ei Kinai, Koji Watanabe, Takahiro Aoki, Daisuke Mizushima, Ikumi Genka, Miwako Honda, Masayuki Chida, Junichi Masuda, Mai Nakamura, Fumihide Kanaya

Abstract

Background: Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in patients with suppressed viral load.

Methods: This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation.

Results: 58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary β2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 µg/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD).

Conclusions: Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary β2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL+DRV/r showed favorable viral efficacy in patients with suppressed viral load.

Trial registration: ClinicalTrials.gov NCT01294761 https://ichgcp.net/clinical-trials-registry/NCT01294761?term=SPARE&rank=2, Umin Clinical Trials Registry UMIN000005116 http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000006083&language=J).

Conflict of interest statement

Competing Interests: T. Naito received research grants from MSD K.K., Janssen Pharmaceutical K.K., and ViiV Healthcare. TF received research grants from ViiV Healthcare and MSD K.K. HM is a co-inventor on a government patent for darunavir as an employee of the U.S. Government under the terms of the Federal Technology Transfer Act. All rights, title, and interest to the patent have been assigned to the Government. SO received research grants from MSD K.K., Abbott Japan, Co., Janssen Pharmaceutical K.K., Pfizer, Co., and Roche Diagnostics K.K. All other authors declare no conflict of interest. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Enrollment, randomization, and disposition of…
Figure 1. Enrollment, randomization, and disposition of patients.
Darunavir/r, ritonavir-boosted darunavir; Lopinavir/r, ritonavir-boosted lopinavir.
Figure 2. Median changes in markers of…
Figure 2. Median changes in markers of renal tubular function between baseline and 48 weeks.
(A) Urinary β2 microglobulin, (B) Urinary albumin, (C) Percent tubular resorption of phosphate, (D) Urinary N-acetyl-β-D-glucosaminidase. RAL, raltegravir; DRV/r, ritonavir-boosted darunavir; LPV/r, ritonavir-boosted lopinavir; TVD, fixed dose of tenofovir/emtricitabine.
Figure 3. Proportion of patients with HIV…
Figure 3. Proportion of patients with HIV RNA
(A) Per protocol analysis. (B) Intention-to-treat analysis. VL, viral load; RAL, raltegravir; DRV/r, ritonavir-boosted darunavir; LPV/r, ritonavir-boosted lopinavir; TVD, fixed dose of tenofovir/emtricitabine.

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