CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

898

High Genetic Diversity of Rifampicin-Resistant Mycobacterium tuberculosis Strains in Botswana Tuelo Mogashoa 1 , Johannes Loubser 2 , Anzaan Dippenaar 3 , Ontlametse T. Bareng 1 , Patience Motshosi 1 , Kedumetse Seru 1 , Tuduetso Molefi 4 , Maruping Maruping 5 , Chawangwa Modongo 6 , Dimpho Otukile 6 , Mpaphi Mbulawa 5 , Simani Gaseitiswe 1 , Rob M. Warren 2 , Sikhulile Moyo 1 , Elizabeth M. Streicher 2 1 Botswana Harvard AIDS Institute Partnership, Gabarone, Botswana, 2 Stellenbosch University, Cape Town, South Africa, 3 University of Antwerp, Antwerp, Belgium, 4 Botswana Ministry of Health, Gaborone, Botswana, 5 Botswana National Tuberculosis Reference Laboratory, Gaborone, Botswana, 6 Victus Global Botswana, Gaborone, Botswana Background: The emergence of drug-resistant Mycobacterium tuberculosis (M.tb) strains remains a threat to tuberculosis(TB) control. For effective TB control, it is important to obtain genetic information on lineages of M.tb and to understand the drug resistance profiles of the circulating strains. This study aimed to describe the genetic diversity and drug resistance profiles of rifampicin-resistant M.tb strains circulating in Botswana using whole genome sequencing (WGS). Methods: This retrospective study utilized 100 M.tb isolates from people diagnosed with Rifampicin-resistant TB (RR-TB) between January 2016-December 2021. Genomic DNA was extracted using the cetyltrimethylammonium bromide (CTAB) method. Library preparation was performed with Rapid Barcoding Kit (SQK-BK110.96), following the manufacturer's instructions. Sequencing was performed on an Oxford Nanopore Technology GridION X5 sequencer using an R9.4 flow cell. TB-profiler was used to identify known M.tb lineages and drug resistance profiles. Univariate and multivariate logistic regression models were used to identify factors associated with unsuccessful TB treatment outcomes. Results: WGS analysis revealed the following drug resistance profiles; MDR (57%: 95% CI; 46.7%-66.9), Pre-XDR (21%, 95% CI:13.5-30.3), RR-TB (21%: 95% CI; 13.5-30.3), and HR-TB (1%:95% CI; 0.2-5.5). Additionally, we identified a high genetic diversity with 3 predominant M.tb lineages: Lineage 4 (62%:95%CI;51.7 71.5), Lineage 1(19%: 95%CI; 11.8-28.1), Lineage 2(18%: 95%CI;11.0-26.9) and Lineage 3(2%:95%CI;2.4-7.0) which was the least common. The most frequently observed mutations for rifampicin, isoniazid, ethambutol, pyrazinamide, and fluoroquinolones were: rpoB Ser450Leu (52%), katG Ser315Thr (60.8%), embA_c.-29_-28delCT, embB Gln497Arg (31%), rrs_n.517C>T (59%), and gyrA Asp90Val(71%), respectively. Bedaquiline and Delamanid resistance-associated mutations were not detected among RR-TB isolates. Residing in rural areas was associated with unsuccessful TB treatment outcomes (adjusted odds ratios: 9.1, 95% CI: 3.0-27.9, p-value<0.001). No specific lineage was associated with any TB treatment outcome. Conclusion: A high genetic diversity and predominance of M.tb lineage four among individuals with RR-TB was observed in Botswana. Data generated from this study provides insights into the genetic diversity and drug resistance mutations present in RR M.tb strains circulating in Botswana. Exposure to PrEP and Safety Monitoring in Pregnancy: Importance of Objective Exposure Measurement Dvora L Joseph Davey 1 , Kalisha Bheemraj 2 , Thokozile R. Malaba 2 , Rufaro Mvududu 2 , Linda-Gail Bekker 3 , Thomas Coates 1 , Landon Myer 2 1 University of California Los Angeles, Los Angeles, CA, USA, 2 University of Cape Town, Cape Town, South Africa, 3 Desmond Tutu HIV Foundation, Cape Town, South Africa Background: To date, TDF/FTC for pre-exposure prophylaxis (PrEP) safety in pregnancy has been based on self-reported adherence or study allocation with no safety studies using objective exposure measures. Methods: The PrEP in pregnancy and postpartum (PrEP-PP) study in Cape Town enrolled pregnant women =>16 years without HIV at their first antenatal care visit followed-up through 12-months postpartum; all women were counselled on HIV risk including oral PrEP (TDF/FTC). In women who reported taking PrEP in the last month, we quantified tenofovir diphosphate (TFV-DP) levels in dried blood spots (DBS). Here we compare pregnancy outcomes in those: (1) self-reporting PrEP use in pregnancy, (2) with objective levels of PrEP use (any TFV-DP detected), (3) missing PrEP exposure data (received prescription but never confirmed PrEP use) using multivariable logistic regression adjusting for maternal age and gestational age at baseline. Results: In 826 women who reported PrEP use during pregnancy with pregnancy outcome data, the median age was 27 years (IQR:23-31), baseline gestation age (GA) was 22 weeks (IQR:14:30); 32% were primigravid. In pregnant women reporting PrEP use in the last 30 days, 181 of 471 (39%)

pregnant women had objective levels of PrEP use (any TFV-DP in DBS). Women with TFV-DP present were older age, >20 weeks GA (vs <20 weeks) at PrEP start, had a partner living with HIV (or unknown serostatus), had higher sex frequency in past month (>5 times vs <5 times or no sex) (p<0.05). Women with missing PrEP exposures had the highest rates of adverse pregnancy outcomes during the study period at 32.6% (18.4% pregnancy loss, 10.4% preterm delivery, 8.7% infant born SGA). In women with TFV-DP in their DBS (n=181), adverse outcomes were significantly lower at overall composite outcome at 17%, including 3.9% had pregnancy loss, 6.6% had preterm delivery, 6.6% had an infant born SGA (Table 1). Correlation between self reported PrEP use and TFV-DP was –0.07 in pregnancy. Conclusion: The proportion of "PrEP-exposed" pregnant women with adverse pregnancy outcomes differed significantly based on how PrEP exposure was defined in the study, highlighting the importance of objective monitoring in pregnancy safety studies as self-reported PrEP use did not correlate with objective levels. Pregnant women who discontinued PrEP had poorest pregnancy outcomes and may require additional interventions for PrEP and pregnancy health. Rapid, cost-effective methods for measuring objective PrEP use are urgently needed. Pharmacokinetic Study Comparing TAF and TDF as PrEP in Pregnant and Postpartum Women in South Africa Dvora L Joseph Davey 1 , Sumaya Dadan 2 , Saye Khoo 3 , Lubbe Wiesner 2 , Landon Myer 2 , Peter L. Anderson 4 , Catherine Orrell 5 1 University of California Los Angeles, Los Angeles, CA, USA, 2 University of Cape Town, Cape Town, South Africa, 3 University of Liverpool, Liverpool, United Kingdom, 4 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 5 Desmond Tutu HIV Foundation, Cape Town, South Africa Background: ARVs for PrEP are effective at preventing HIV. However, among pregnant women receiving tenofovir disoproxil fumarate and emtricitabine (TDF/FTC), lower tenofovir (TFV) and intracellular tenofovir-diphosphate (TFV-DP) concentrations in red blood cells have been found compared to postpartum periods. No studies have been conducted to establish concentrations of TFV-DP after administration of tenofovir alafenamide (TAF) in pregnant and postpartum individuals. Methods: Between June 2022 and March 2023, we recruited eligible and consenting pregnant women from a cohort study in Cape Town, South Africa. We randomized participants in the 2nd trimester 1:1 to daily dosing of tenofovir alafenamide-emtricitabine (TAF/FTC) or TDF/FTC. Participants had 8 weekly study visits and bloods drawn (plasma, dried blood spots [DBS]) during pregnancy and again postpartum. Adherence was monitored using video directly observed therapy. We compared TFV-DP concentrations between TDF and TAF for pregnancy vs. postpartum in both DBS and PBMCs including geometric mean ratios (GMR) for log concentrations and 95% CIs (STATA v18). Results: We evaluated 37 paired pregnancy and postpartum individuals; 19 in the TAF arm and 18 in the TDF arm. Two participants did not adhere to the protocol and were excluded. Median age was 28.2 years (IQR=23-32); median gestation age at PrEP start/study baseline was 24 weeks (IQR=21-24 weeks). In TAF, median concentrations of TFV-DP in DBS were 51% higher in postpartum and 1% higher in PBMCs when compared to pregnancy. In TDF, median concentrations of TFV-DP in DBS were 12% higher in postpartum and 35% higher in PBMCs samples vs. pregnancy (Table 1). GMR for postpartum vs. pregnancy for TFV-DP was 1.68 (1.61-1.76) for TAF DBS, and 1.01 (0.94-1.07) for TAF PBMCs. GMR for TFV-DP in TDF samples was 1.62 (1.53-1.71) for DBS and 1.39 (1.34-1.45) in PBMCs. In TAF samples, median FTC-TP was 9.42 (IQR:6.47 14.0) in pregnancy and 10.45 (6.6-14.45) in postpartum (GMR=1.15; 1.11-1.99). Comparing TAF vs. TDF PBMCs, GMR was 30.1 (25.0-36.2), similar in pregnant and postpartum samples. No safety related adverse events were found. Conclusion: Our findings demonstrate high concentrations of TFV-DP in PBMC in pregnancy and postpartum among women receiving TAF suggesting PrEP efficacy is retained. DBS adherence benchmarks for daily dosing were established for TAF in pregnant and postpartum in African women. Efficacy

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