CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

144LB RIFAPENTINE PHARMACOKINETICS AND SAFETY IN PREGNANT WOMEN WITH AND WITHOUT HIV ON 3HP Jyoti S. Mathad 1 , Radojka M. Savic 2 , Paula Britto 3 , Lubbe Wiesner 4 , Ellen Townley 5 , Nahida Chakhtoura 6 , Sarah Bradford 7 , Sandesh Patil 8 , Tichaona Vhembo 9 , Dominique Lespinasse 10 , Deborah Langat 11 , Peerawong Werarak 12 , Portia Kamthunzi 13 , Amita Gupta 14 , Kelly E. Dooley 14 1 Weill Cornell Medicine, New York, NY, USA, 2 University of California San Francisco, San Francisco, CA, USA, 3 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 4 University of Cape Town, Cape Town, South Africa, 5 NIAID, Bethesda, MD, USA, 6 National Institute of Child Health and Human Development, Bethesda, MD, USA, 7 FHI 360, Durham, NC, USA, 8 Byramjee Jeejeebhoy Government Medical College, Pune, India, 9 University of Zimbabwe, Harare, Zimbabwe, 10 GHESKIO, Port-au- Prince, Haiti, 11 Kenya Medical Research Institute, Kericho, Kenya, 12 Siriraj Hospital, Bangkok, Thailand, 13 University of North Carolina Project–Malawi, Lilongwe, Malawi, 14 Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: Pregnancy increases the risk of progressing from latent tuberculosis infection (LTBI) to active TB. A 3-month TB-prevention regimen of weekly isoniazid and rifapentine (3HP) shows excellent safety and adherence in non-pregnant people, including those with HIV. We hypothesized that the pharmacokinetics (PK) of rifapentine (RPT) in pregnant women taking 3HP would be comparable to non-pregnant adults and well-tolerated. Methods: IMPAACT 2001 is a Phase I/II study evaluating the PK and safety of 3HP among pregnant women with or without HIV, who had LTBI or a household contact with active pulmonary TB (NCT02651259). Sites were in Haiti, Kenya, Malawi, Thailand, and Zimbabwe. Cohort 1 had dosing and PK sampling in the 2nd and 3rd trimesters; Cohort 2 in the 3rd trimester and postpartum. Isoniazid and RPT were provided at standard doses of 900mg weekly. PK samples were collected with the 1st (predose, 0.5h, 1h, 2h, 4h, 5h, 8h, 12h, 24h, 48h, 72h post- dose) and 12th doses (predose, 1h, 4h, 24h, 48h post-dose). Primary objectives were to estimate the population PK of RPT during pregnancy and post-partum using non-linear mixed effects modeling, and to describe maternal-infant safety outcomes. Results: We enrolled 50 pregnant women, 25 per cohort. Twenty women had HIV; all were taking efavirenz (EFV)-based antiretroviral therapy (median CD4:510 cells/mm 3 ). All women completed the 3HP regimen. There were no drug-related SAE and no cases of active TB in women or their infants. There was one maternal and fetal death by abruptio placentae from trauma. Among women without HIV, oral clearance (CL/F) of RPT was 36% lower during pregnancy (1.24 L/h) than post-partum (1.68 L/h), with an area under the concentration-time curve (AUC) of 736 and 618 mg*hr/L, similar to historical non-pregnant controls. In women with HIV, CL/F was the same during pregnancy and postpartum (1.60 vs.1.61 L/ hr), which was 34% higher (p<0.001) compared to pregnant women without HIV, resulting in a lower AUC of 512 mg*h/L. Conclusion: Pregnancy does not appear to increase RPT clearance; thus, there is no need for dose adjustment of 3HP in pregnancy. Among women with HIV taking EFV, however, clearance of RPT was higher than expected during pregnancy. Exposures remained in the expected therapeutic range. Initial tolerability and safety results from this small trial are encouraging, given limited options for TB prophylaxis in pregnancy, but larger studies will be needed to characterize its safety in pregnancy definitively.

community, in particular men and youth, are critical for reaching individuals who might otherwise be reticent to take up standard facility-based testing services. An approach focused on identifying persons unaware of their HIV- positive status in combination with monitoring the PUF has the potential to achieve the UNAIDS 90-90-90 target. 143LB EFFECTIVENESS OF 3HP ANNUALLY VS ONCE FOR HIV-POSITIVE PEOPLE: THE WHIP3TB TRIAL Gavin Churchyard 1 , Vicky Cardenas 2 , Violet Chihota 2 , Kathryn Mngadi 2 , Modulakgotla Sebe 1 , William L. Brumskine 3 , Salome Charalambous 1 , Neil A. Martinson 4 , Getnet Yimer 5 , Alberto L. Garcia-Basteiro 6 , Leeanne Masilela 2 , Susan Van Den Hof 7 , Richard E. Chaisson 8 , Alison Grant 9 , Katherine Fielding 9 1 The Aurum Institute, Johannesburg, South Africa, 2 The Aurum Institute, Parktown, South Africa, 3 The Aurum Institute, Rustenburg, South Africa, 4 University of the Witwatersrand, Gauteng, South Africa, 5 Addis Ababa University, Addis Ababa, Ethiopia, 6 Manhica Health Research Centre, Barcelona, Spain, 7 KNCV Tuberculosis Foundation, Den Haag, Netherlands, 8 Johns Hopkins University, Baltimore, MD, USA, 9 London School of Hygiene & Tropical Medicine, London, UK Background: Weekly isoniazid (900mg) and rifapentine (900mg) for 12 weeks (3HP) has similar efficacy to 6 months of daily isoniazid (6H) as TB preventive therapy. We compared treatment completion rates and effectiveness of 3HP vs. 6H and the effectiveness of 3HP given annually vs. once among HIV-positive people. (NCT02980016) Methods: HIV-positive people in South Africa, Ethiopia and Mozambique aged ≥2 years, without active TB and on antiretroviral therapy (ART) for ≥3 months or ineligible were randomized 9:9:2 to periodic (annual) 3HP (p3HP), 3HP, or 6H. Participants in the 3HP/p3HP and 6H arms were followed for 24 and 12months, respectively; all were seen monthly for the first three months of each participation year. Medication doses were directly observed at dispensing visits and otherwise self-administered. Participants in the 6H armwere dispensed 3 months treatment at month 3. Participants were screened for TB with symptoms, chest X-ray and sputum culture after 12 and 24 months. Completion of the initial treatment course in the combined 3HP/p3HP arms vs. 6H was compared using pill counts. TB incidence and all-cause mortality over 12 months was compared in the 3HP and 6H arms, and TB incidence, all-cause mortality, and permanent discontinuation of 3HP for adverse events over 24 months was compared in the p3HP and 3HP arms. Results: Between November 2016 and November 2017, 4593 participants were screened, 4027 enrolled and 4014 analysed. The median age was 41 years (19 (0.5%) <18 years), all were on ART, 70%were female, 38%were QuantiFERON-TB GOLD Plus positive; 63%, 22% and 15%were from South Africa, Ethiopia and Mozambique, respectively. Treatment completion in the combined 3HP (n=3610) and 6H (n=404) arms was 90.4% versus 50.5% (risk ratio: 1.79; 95%CI:1.62-1.79). TB incidence and mortality by study arm are shown in the table. TB incidence and mortality frommonth 0 to month 12 was similar in the 3HP and 6H arms. TB incidence over 24 months and frommonth 12 to month 24 was similar in the p3HP (n=1808) and 3HP (n=1802) arms. Over 24 months, TB incidence among QuantiFERON Plus positive participants, incidence of rifampicin resistant TB, and mortality were similar in the p3HP and 3HP arms. Treatment discontinuation in the p3HP and 3HP arms was 1.2% vs. 0.6% (OR2.11, 95%CI:0.95-5.02). Conclusion: Treatment completion was higher in the 3HP arms vs. 6H. In high TB transmission settings, annual 3HP did not provide additional benefit to people receiving ART.

Oral Abstracts

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CROI 2020