While typical dosing of DTG is 50 mg daily, induction of the drug’s metabolism by rifampin prohibits use of once daily dolutegravir. These studies show that DTG dosed at 50 mg BID is a safe and effective therapy option for HIV patients on Rifampin treatment for TB.
Safety, tolerability, and pharmacokinetics of the HV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: Results of a phase 1 study among healthy subjects.
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Study Design
This was a phase 1, open-label, fixed-sequence study conducted in healthy adults. Participants received 50mg dolutegravir (DTG) once daily for 7 days, followed by 50mg DTG BID for 7 days, followed by 50mg DTG BID plus 600mg rifampin (RIF) once daily for 14 days. Plasma samples were collected for DTG at the end of each dosing period.
In part 2: Participants received 50mg dolutegravir (DTG) QD for 7 days, followed by 50mg DTG QD plus 300mg rifabutin (RBT) QD for 14 days. Plasma samples were collected for DTG at the end of each dosing period.
Study Results
Reduced DTG concentrations were observed with addition of RIF 600mg QD to DTG 50mg BID. The geometric mean ratio (90% confidence interval) for AUC, Cmax and Cmin were 0.46 (90%CI, 0.38-0.55), 0.57 (90%CI, 0.49-0.65) and 0.28 (90%CI, 0.23-0.34) respectively, compared to DTG 50mg BID alone. However, plasma concentrations of DTG 50mg BID plus RIF 600mg QD were similar to or higher than those achieved when DTG 50mg was given once daily alone (AUC0-24, 1.33 (90%CI 1.15-1.53), Cmax, 1.18 (90%CI 1.03-1.37) and Ct, 1.22 (90% CI 1.01-1.48)).
Plasma concentrations were similar when DTG 50mg QD was administered with and without RBT 300mg QD. The geometric mean ratio (90% confidence interval) for AUC was 0.95 (90%CI, 0.82-1.10), Cmax 1.16 (90%CI, 0.98-1.37) and Cmin 0.70 (90%CI, 0.57-0.87). While the trough concentrations for DTG were reduced by approximately 30%, they were still higher than the protein-adjusted IC50 of 0.016 mcg/ml against HIV-1.
Study Conclusions
A dose adjustment of TIVICAY (dolutegravir) to 50 mg twice daily is recommended in treatment-naïve or treatment experienced, INSTI-naïve patients.
Alternatives to rifampin should be used where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.
Based on virologic responses observed in DTG doses ranging from 10-50 mg QD in the SPRING-1 trial, the 30% reduction in DTG trough concentrations when co-administered with RBT is unlikely to lower clinical efficacy of DTG. No dose adjustments are required.
References
Dooley KE, Sayre P, Borland J. Safety, tolerability, and pharmacokinetics of the hv integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. Jaids: Journal Of Acquired Immunodeficiency Syndrome. 2013; 1: 21-26.
Dolutegravir versus Rifampin
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Study Design
Participants on rifampin-based tuberculosis (TB) treatment for up to 8 weeks were randomized (3:2) to receive dolutegravir (DTG 50mg twice daily during and for 2 weeks post-TB therapy, followed by 50mg once daily [OD]) or efavirenz (EFV 600mg OD), with 2 investigator-selected NRTIs for 52 weeks. For this Week 24 interim analysis, the proportion of subjects with plasma HIV-1-RNA <50 c/mL was derived using the FDA Snapshot algorithm in the intent to treat exposed (ITT-E) population.
Study Results
Of 113 subjects enrolled, 69 were randomized to DTG and 44 to EFV. Median baseline HIV-1 RNA and CD4+ cell counts were 5.10 log10 c/mL and 208 cells/μL in the DTG arm and 5.24 log10 c/mL and 202 cells/μL in the EFV arm. The proportions of subjects with HIV-1-RNA <50 c/mL at Week 24 were 56/69 (81%) (95% CI: 72%, 90%) in the DTG arm and 39/44 (89%) (95% CI: 79%, 98%) in the EFV arm. Median CD4+ cell increases at Week 24 were 146 cells/μL (IQR: 71, 214) for DTG and 93 cells/μL (IQR: 47, 178) for EFV.
Study Conclusions
Results from this study show that DTG 50 mg twice daily appears to be effective and well-tolerated in HIV/TB co-infected adults receiving RIF-based TB therapy. Rates of immune reconstitution inflammatory syndrome (IRIS) were low. There were no new toxicity signals for DTG and no discontinuations due to liver events. These data support the use of DTG based regimen in HIV/TB co-infection.
References
Dooley, K, Kaplan, R, Mwelase, N. Safety and efficacy of dolutegravir-based art in tb/hiv coinfected adults at week 24. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018.
Safety, tolerability, and pharmacokinetics of the HV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: Results of a phase 1 study among healthy subjects.
^
Study Design
This was a phase 1, open-label, fixed-sequence study conducted in healthy adults. Participants received 50mg dolutegravir (DTG) once daily for 7 days, followed by 50mg DTG BID for 7 days, followed by 50mg DTG BID plus 600mg rifampin (RIF) once daily for 14 days. Plasma samples were collected for DTG at the end of each dosing period.
In part 2: Participants received 50mg dolutegravir (DTG) QD for 7 days, followed by 50mg DTG QD plus 300mg rifabutin (RBT) QD for 14 days. Plasma samples were collected for DTG at the end of each dosing period.
Study Results
Reduced DTG concentrations were observed with addition of RIF 600mg QD to DTG 50mg BID. The geometric mean ratio (90% confidence interval) for AUC, Cmax and Cmin were 0.46 (90%CI, 0.38-0.55), 0.57 (90%CI, 0.49-0.65) and 0.28 (90%CI, 0.23-0.34) respectively, compared to DTG 50mg BID alone. However, plasma concentrations of DTG 50mg BID plus RIF 600mg QD were similar to or higher than those achieved when DTG 50mg was given once daily alone (AUC0-24, 1.33 (90%CI 1.15-1.53), Cmax, 1.18 (90%CI 1.03-1.37) and Ct, 1.22 (90% CI 1.01-1.48)).
Plasma concentrations were similar when DTG 50mg QD was administered with and without RBT 300mg QD. The geometric mean ratio (90% confidence interval) for AUC was 0.95 (90%CI, 0.82-1.10), Cmax 1.16 (90%CI, 0.98-1.37) and Cmin 0.70 (90%CI, 0.57-0.87). While the trough concentrations for DTG were reduced by approximately 30%, they were still higher than the protein-adjusted IC50 of 0.016 mcg/ml against HIV-1.
Study Conclusions
A dose adjustment of TIVICAY (dolutegravir) to 50 mg twice daily is recommended in treatment-naïve or treatment experienced, INSTI-naïve patients.
Alternatives to rifampin should be used where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.
Based on virologic responses observed in DTG doses ranging from 10-50 mg QD in the SPRING-1 trial, the 30% reduction in DTG trough concentrations when co-administered with RBT is unlikely to lower clinical efficacy of DTG. No dose adjustments are required.
References
Dooley, K, Kaplan, R, Mwelase, N. Safety and efficacy of dolutegravir-based art in tb/hiv coinfected adults at week 24. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018.
Dolutegravir versus Rifampin
^
Study Design
Participants on rifampin-based tuberculosis (TB) treatment for up to 8 weeks were randomized (3:2) to receive dolutegravir (DTG 50mg twice daily during and for 2 weeks post-TB therapy, followed by 50mg once daily [OD]) or efavirenz (EFV 600mg OD), with 2 investigator-selected NRTIs for 52 weeks. For this Week 24 interim analysis, the proportion of subjects with plasma HIV-1-RNA <50 c/mL was derived using the FDA Snapshot algorithm in the intent to treat exposed (ITT-E) population.
Study Results
Of 113 subjects enrolled, 69 were randomized to DTG and 44 to EFV. Median baseline HIV-1 RNA and CD4+ cell counts were 5.10 log10 c/mL and 208 cells/μL in the DTG arm and 5.24 log10 c/mL and 202 cells/μL in the EFV arm. The proportions of subjects with HIV-1-RNA <50 c/mL at Week 24 were 56/69 (81%) (95% CI: 72%, 90%) in the DTG arm and 39/44 (89%) (95% CI: 79%, 98%) in the EFV arm. Median CD4+ cell increases at Week 24 were 146 cells/μL (IQR: 71, 214) for DTG and 93 cells/μL (IQR: 47, 178) for EFV.
Study Conclusions
Results from this study show that DTG 50 mg twice daily appears to be effective and well-tolerated in HIV/TB co-infected adults receiving RIF-based TB therapy. Rates of immune reconstitution inflammatory syndrome (IRIS) were low. There were no new toxicity signals for DTG and no discontinuations due to liver events. These data support the use of DTG based regimen in HIV/TB co-infection.
References
Dooley, K, Kaplan, R, Mwelase, N. Safety and efficacy of dolutegravir-based art in tb/hiv coinfected adults at week 24. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018.
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