Willem D F Venter1, Michelle Moorhouse2, Simiso Sokhela2, Celicia Serenata2, Godspower Akpomiemie2, Ambar Qavi3, Nonkululeko Mashabane2, Natasha Arulappan2, Joel W Sim3, Phumla Z Sinxadi4, Lubbe Wiesner4, Ellisha Maharaj2, Carole Wallis5, Tom Boyles2, David Ripin6, Sarah Stacey7, Gila Chitauri8, Andrew Hill9. 1. Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Electronic address: fventer@wrhi.ac.za. 2. Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. 3. Faculty of Medicine, Imperial College London, London, UK. 4. Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. 5. BARC, Lancet Laboratories, Johannesburg, South Africa. 6. Clinton Health Access Initiative, Boston, MA, USA. 7. Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Division of Infectious Diseases, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa. 8. Division of Infectious Diseases, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa. 9. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Abstract
BACKGROUND: Pilot studies suggest that ritonavir-boosted darunavir could show high efficacy at doses below those currently approved. We investigated whether switch to 400 mg of darunavir boosted with 100 mg ritonavir once daily could show equivalent efficacy to continuation of ritonavir-boosted lopinavir (a protease inhibitor commonly used in low-income and middle-income countries) for individuals with HIV RNA suppression. METHODS: In the WRHI 052 study, a randomised, parallel-group, open-label, non-inferiority phase 3 trial, adults who were HIV-1 positive were enrolled in Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa. Eligible participants were 18 years or older, who tolerated ritonavir-boosted lopinavir in combination with two nucleoside analogues (standard of care) for 6 months or more, and had plasma HIV-1 RNA of less than 50 copies per mL within 60 days of enrolment. We randomly assigned participants (1:1), using a computer-generated randomisation plan, to switch to darunavir (400 mg) boosted with ritonavir (100 mg) once daily or remain on ritonavir-boosted lopinavir (800 mg [plus 200 mg ritonavir]), with nucleoside analogues left unchanged. The primary endpoint was the proportion of patients with less than 50 HIV-1 RNA copies per mL at week 48 (US Food and Drug Administration snapshot algorithm; non-inferiority margin -4%). Primary and safety analyses included participants receiving at least one dose of darunavir boosted withritonavir. This trial is registered with ClinicalTrials.gov, number NCT02671383. FINDINGS:Between June 30, 2016, and June 15, 2017, 148 participants were assigned toritonavir-boosted darunavir 400 mg and 152 continued on their lopinavir-containing regimen. Four (3%) patients in the darunavir group and three (2%) in the lopinavir group discontinued before week 48. At week 48, darunavir was non-inferior to lopinavir for the primary outcome (142 [96%] of 148 participants on darunavir had <50 HIV-1 RNA copies per mL vs 143 [94%] of 152 participants on lopinavir; difference 1·9% [95% CI -3·4 to 7·3]), with a predefined margin of -4%. More participants taking darunavir (30 [20%] participants) had drug-related adverse events than those on lopinavir (eight [5%]), but the adverse events were generally asymptomatic and resolved when switching back to lopinavir. Elevated liver transaminase in three (1%; one symptomatic) darunavir participants led to study withdrawal; all transaminase elevations resolved on restarting lopinavir. INTERPRETATION: Low-dose ritonavir-boosted darunavir might be a safe and efficacious switch option to maintain HIV suppression for patients on lopinavir. However, an adequately powered and designed study in viraemic participants is needed. FUNDING: South African Medical Research Council, United States Agency for International Development, and US National Institute of Allergy and Infectious Diseases.
RCT Entities:
BACKGROUND: Pilot studies suggest that ritonavir-boosted darunavir could show high efficacy at doses below those currently approved. We investigated whether switch to 400 mg of darunavir boosted with 100 mg ritonavir once daily could show equivalent efficacy to continuation of ritonavir-boosted lopinavir (a protease inhibitor commonly used in low-income and middle-income countries) for individuals with HIV RNA suppression. METHODS: In the WRHI 052 study, a randomised, parallel-group, open-label, non-inferiority phase 3 trial, adults who were HIV-1 positive were enrolled in Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa. Eligible participants were 18 years or older, who tolerated ritonavir-boosted lopinavir in combination with two nucleoside analogues (standard of care) for 6 months or more, and had plasma HIV-1 RNA of less than 50 copies per mL within 60 days of enrolment. We randomly assigned participants (1:1), using a computer-generated randomisation plan, to switch to darunavir (400 mg) boosted with ritonavir (100 mg) once daily or remain on ritonavir-boosted lopinavir (800 mg [plus 200 mg ritonavir]), with nucleoside analogues left unchanged. The primary endpoint was the proportion of patients with less than 50 HIV-1 RNA copies per mL at week 48 (US Food and Drug Administration snapshot algorithm; non-inferiority margin -4%). Primary and safety analyses included participants receiving at least one dose of darunavir boosted with ritonavir. This trial is registered with ClinicalTrials.gov, number NCT02671383. FINDINGS: Between June 30, 2016, and June 15, 2017, 148 participants were assigned to ritonavir-boosted darunavir 400 mg and 152 continued on their lopinavir-containing regimen. Four (3%) patients in the darunavir group and three (2%) in the lopinavir group discontinued before week 48. At week 48, darunavir was non-inferior to lopinavir for the primary outcome (142 [96%] of 148 participants on darunavir had <50 HIV-1 RNA copies per mL vs 143 [94%] of 152 participants on lopinavir; difference 1·9% [95% CI -3·4 to 7·3]), with a predefined margin of -4%. More participants taking darunavir (30 [20%] participants) had drug-related adverse events than those on lopinavir (eight [5%]), but the adverse events were generally asymptomatic and resolved when switching back to lopinavir. Elevated liver transaminase in three (1%; one symptomatic) darunavirparticipants led to study withdrawal; all transaminase elevations resolved on restarting lopinavir. INTERPRETATION: Low-dose ritonavir-boosted darunavir might be a safe and efficacious switch option to maintain HIV suppression for patients on lopinavir. However, an adequately powered and designed study in viraemic participants is needed. FUNDING: South African Medical Research Council, United States Agency for International Development, and US National Institute of Allergy and Infectious Diseases.
Authors: Maren Kummerow; Erica J Shaddock; Kerstin Klipstein-Grobusch; Roos B Barth; Diederick E Grobbee; Francois D F Venter; Charles Feldman; Alinda Vos Journal: South Afr J HIV Med Date: 2019-09-26 Impact factor: 2.744
Authors: Sarah E van Riel; Kerstin Klipstein-Grobusch; Roos E Barth; Diederick E Grobbee; Charles Feldman; Erica Shaddock; Sarah L Stacey; Willem D F Venter; Alinda G Vos Journal: South Afr J HIV Med Date: 2021-08-17 Impact factor: 2.744
Authors: Alinda G Vos; Caitlin N Dodd; Eveline M Delemarre; Stefan Nierkens; Celicia Serenata; Diederick E Grobbee; Kerstin Klipstein-Grobusch; W D Francois Venter Journal: Front Immunol Date: 2021-07-05 Impact factor: 7.561
Authors: Alinda G Vos; Klariska Hoeve; Roos E Barth; Joyce Peper; Michelle Moorhouse; Nigel J Crowther; Willem D F Venter; Diederick E Grobbee; Michiel L Bots; Kerstin Klipstein-Grobusch Journal: Retrovirology Date: 2019-12-03 Impact factor: 4.602