Although HP decreased DTG bioavailability, which was associated with a modest decrease in trough levels, all viral loads were suppressed. DTG may be co- administered with 3HP without dose adjustment.
Dolutegravir versus Isoniazid/Rifapentine
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Study Design
This was an open label intrasubject drug interaction study involving HIV-negative healthy volunteers comprising of 2 phases. (n=4) Subjects received dolutegravir (DTG) 50mg daily on days 1-19 of the study, days 1-4 being given alone. While on days 5-19 subjects concurrently received once weekly isoniazid (INH) and rifapentine (RPT) on days 5, 12 and 19. DTG levels were measured at all PK visits on days 4, 14, and 19. INH + RPT levels were measured only on day 19. Geometric mean ratios with 90% confidence intervals were compared between PK days during the study. Adverse events were graded based on a study defined toxicity scale.
Study Results
Based on GMRs and 90% confidence intervals, there was a 46% decrease in DTG exposure on day 14 vs. Day 4 90% CI (0.27-1.10) following INH + RPT initiation. On day 19 exposure to RPT and its active metabolite were similar to reference PK data, but INH exposure was 67-92% higher than expected in the 2 subjects who developed AEs.
This combination resulted in a number of adverse events. The study was stopped prematurely
Study Conclusions
Per the authors, clinically significant PK interactions are expected and the combination of dolutegravir with isoniazid and rifapentine should be avoided in patients being treated for latent tuberculosis infection and while concurrently on ARV therapy
References
Brooks KM, Pau AK, George JM, Kellogg A, McLaughlin M, McManus M, Kumar P. Early termination of a pk study between dolutegravir and weekly isoniazid/rifapentine. Headache. 2017; : 1.
DTG Vs. Isoniazid/rifapentine (HP)
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Study Design
HIV infected adults with undetectable viral load on efavirenz (EFV)- based regimens were recruited into 3 groups. All received DTG in place of EFV for 8 weeks, then began 12 once weekly rifapentine/isoniazid dose ( HP); after HP completion, all participants were followed 4 more weeks. Viral loads were measured at baseline and weeks 11 and 24. Groups 1A (n=12) and 1B (n=18) had intensive DTG PK sampling performed at week 8 (pre-HP), then weeks 11 and 16 following the 3rd and 8th doses of HP. Group 2 (n=30) were treated with the same schedule and had sparse DTG PK sampling
at weeks 8, 11 and 16. Primary endpoints were 1) grade >3 AE and 2) population PK parameters of DTG with or without HP
Study Results
Of the 60 participants who received 3HP, 43 (70%) were female, median (IQR) age was 40 (35-48) years, all were black African, median (IQR)
CD4 was 683 (447-935) cells/mm3, and median (IQR) BMI was 28.9 (24.0-32.9) kg/m2. All participants received ≥6 HP doses at the time of this report. ThreeGrade 3 AE occurred (2 elevated creatinine, 1 hypertension). HIV viral loads at baseline, day 58 (pre-HP), day 72 (3rd HP dose) and day 168 (post-HP) were all <40 c/mL. Table 1 shows Group 1A and 1B PK results. The geometric mean (GM) trough concentration of DTG on Day 58 (pre-HP) was 1003 ug/mL (5th-95th %ile: 500-2080), and during HP treatment 546 (134-1616) with all trough levels but one above DTG IC90 of 64 ug/mL; Table). Overall, HP administration decreased DTG bioavailability by 29% (RSE 13%) (+18%, -37% and -35% for week 1, 3 and 8), while clearance remained unchanged.
Study Conclusions
The authors concluded that co-administration of DTG and HP was well-tolerated, with no HP-related Grade >3 AEs. Although HP decreased DTG bioavailability, which was associated with a modest decrease in trough levels, all trough levels but one were above the DTG IC90. All viral loads were suppressed. DTG may be co- administered with 3HP without dose adjustment.
References
Churchyard, G, Savic, R, Gupte, A, Marzinke, M, Zhang, N, Edward, V, etc.. Safety & pk of weekly rifapentine/isoniazid (3hp) in adults with hiv on dolutegravir. Conference On Retroviruses And Opportunistic Infections. 2019; : .
Dolutegravir versus Isoniazid/Rifapentine
^
Study Design
This was an open label intrasubject drug interaction study involving HIV-negative healthy volunteers comprising of 2 phases. (n=4) Subjects received dolutegravir (DTG) 50mg daily on days 1-19 of the study, days 1-4 being given alone. While on days 5-19 subjects concurrently received once weekly isoniazid (INH) and rifapentine (RPT) on days 5, 12 and 19. DTG levels were measured at all PK visits on days 4, 14, and 19. INH + RPT levels were measured only on day 19. Geometric mean ratios with 90% confidence intervals were compared between PK days during the study. Adverse events were graded based on a study defined toxicity scale.
Study Results
Based on GMRs and 90% confidence intervals, there was a 46% decrease in DTG exposure on day 14 vs. Day 4 90% CI (0.27-1.10) following INH + RPT initiation. On day 19 exposure to RPT and its active metabolite were similar to reference PK data, but INH exposure was 67-92% higher than expected in the 2 subjects who developed AEs.
This combination resulted in a number of adverse events. The study was stopped prematurely
Study Conclusions
Per the authors, clinically significant PK interactions are expected and the combination of dolutegravir with isoniazid and rifapentine should be avoided in patients being treated for latent tuberculosis infection and while concurrently on ARV therapy
References
Churchyard, G, Savic, R, Gupte, A, Marzinke, M, Zhang, N, Edward, V, etc.. Safety & pk of weekly rifapentine/isoniazid (3hp) in adults with hiv on dolutegravir. Conference On Retroviruses And Opportunistic Infections. 2019; : .
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