CROI 2019 Abstract eBook
Grade 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. Conclusion: 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.
82 EARLY BACTERICIDAL ACTIVITY OF HIGH-DOSE ISONIAZID AGAINST MULTIDRUG-RESISTANT TB Kelly E. Dooley 1 , Sachiko Miyahara 2 , Florian von Groote-Bidlingmaier 3 , Xin Sun 2 , Richard Hafner 4 , Susan L. Rosenkranz 5 , Eric Nuermberger 1 , Laura E. Moran 6 , Kathleen Donahue 5 , Susan Swindells 7 , Andreas H. Diacon 3 , for the ACTG A5312 Study Team 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Harvard University, Boston, MA, USA, 3 TASK Applied Science, Cape Town, South Africa, 4 DAIDS, NIAID, Bethesda, MD, USA, 5 Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA, 6 Social & Scientific Systems, Silver Spring, MD, USA, 7 University of Nebraska Medical Center, Omaha, NE, USA Background: High-dose isoniazid (INH) may be useful in treating multidrug- resistant tuberculosis (MDR-TB), particularly when INH resistance is mediated by inhA mutations. Although the World Health Organization (WHO) recommends ‘high-dose’ INH as part of the new shorter MDR-TB regimen, the optimal dose and its efficacy are not established. Methods: AIDS Clinical Trials Group (ACTG) A5312 is a Phase 2A randomized, open-label trial in which individuals with smear-positive pulmonary MDR-TB with INH resistance mediated by an inhA mutation (Group 1) were randomized to receive INH doses of 5, 10 or 15 mg/kg daily for 7 days. Controls with drug- sensitive TB (Group 2) received the standard INH dose of 5 mg/kg/day. Sputum cultures were collected daily, beginning at baseline. The early bactericidal activity of INH, estimated as the average daily change in log10 colony forming units (CFU) on solid media (EBACFU0-7) or average daily change in time to positivity (TTP) in hours on liquid media (EBATTP0-7) over 7 days of treatment was estimated using nonlinear mixed effects models. Safety data were collected from study entry through Day 21. Results: 59 participants (43 in Group 1, 16 in Group 2) were enrolled, all in South Africa. The majority (73%) were men, median age was 32 years, 20%were HIV co-infected, and 88% had cavitary lung disease. 58/59 (98%) completed study treatment (one withdrew consent in the 15 mg/kg arm). Eight participants had 9 grade 3 (and no grade 4) adverse events (fever, pain, dyspnea, pneumothorax (2), anemia (4)), all unrelated or unlikely to be related to study drugs. Mean EBACFU0-7 in Group 1 at doses of 5, 10 and 15 mg/kg was 0.07, 0.17 and 0.22 log10CFU/mL/day, respectively; and in Group 2 was 0.16 log10CFU/mL/ day (Figure). Mean EBATTP0-7 in Group 1 (5, 10, 15 mg/kg doses) was 3, 7, 11 hours/day, and in Group 2 was 10 hours/day (Figure). Median minimal inhibitory concentrations in 90 patients screened for study participation were 1 mg/L for inhA-mutated and 0.2 mg/L for drug-sensitive strains. Conclusion: INH had substantial EBA against Mycobacterium tuberculosis strains with inhA mutations among patients with MDR-TB, provided it was dosed at 10-15 mg/kg, supporting WHO recommendations for high-dose INH in this population. Activity at these doses was similar to the standard 5 mg/kg dose in drug-sensitive TB. Longer-term tolerability, plus efficacy of high-dose INH against strains with katG mutations require further study.
81LB PHARMACOKINETICS AND SAFETY OF ADJUSTED DARUNAVIR/RITONAVIR WITH RIFAMPIN IN PLWH Ismaeel Ebrahim , Gary Maartens, Wynand Smythe, Catherine Orrell, Lubbe Wiesner, Helen Mcilleron University of Cape Town, Cape Town, South Africa Background: Darunavir (DRV)/ritonavir(r) is better tolerated than lopinavir (LPV)/r and has a higher genetic barrier to resistance. Co-administration of DRV/r with rifampin (RIF), the key component of first-line TB treatment, is currently contraindicated as significant reductions in DRV exposures are expected; this has been a barrier to the use of DRV/r in resource-limited settings where TB is endemic. We aimed to evaluate the safety and pharmacokinetics (PK) of adjusted doses of DRV/r in PLWH. Methods: We enrolled virologically suppressed participants on a second- line DRV/r regimen without TB. Based on data from a Physiologically-Based PK model, we selected two adjusted doses of DRV/r (1600/200 mg daily and 800/100 mg 12 hourly) with RIF for comparison to plasma exposures with DRV/r 800/100 mg daily without RIF, in a cross-over design. Baseline DRV steady state PK was determined and RIF added for 7 days, then the dose of r was increased to 200 mg; 7 days later the dose of DRV was increased; after another 7 days participants were crossed over to the alternative adjusted DRV dose. DRV was measured in plasma samples after observed doses at baseline and after each dose adjustment. Non-compartmental analysis was used to estimate the PK measures. Clinical adverse events, ALT, and bilirubin were monitored every 2 to 3 days during treatment with RIF. Results: Seventeen of a planned 28 PLWH were enrolled and started on study treatment before the study was stopped due to high rates of hepatotoxicity. Only 4 participants completed the study. Six (35%) of the participants were withdrawn for DAIDS grade 3 (n=3) or 4 (n=3) ALT elevations developing after 9-12 days of RIF; 3 participants were symptomatic. Hepatotoxicity resolved in all cases after withdrawal of study treatment and participants were successfully re-established on their standard of care ART regimen. The PK parameters are shown in table 1. Trough concentrations were below the protein-adjusted EC50 of 200 ng/mL in 2 participants in the QD group adjusted dose group on RIF. Conclusion: Adjusted doses of DRV/r with RIF were associated with unacceptable risk of hepatotoxicity and there was a marked reduction in DRV trough concentrations with the QD adjusted dose in our study.
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