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Importance: Nonresponse to hepatitis B vaccine is common among people with HIV, resulting in vulnerability to infection with hepatitis B virus (HBV)., Objective: To compare the seroprotection response achieved with a 2-dose (noninferiority, 10% margin) and a 3-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine) vs a conventional 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine) in people with HIV and prior nonresponse to HepB-alum vaccine., Design, Setting, and Participants: This phase 3, open-label, randomized clinical trial included people with HIV receiving antiretroviral therapy (CD4 cell count ≥100 cells/μL and HIV RNA <1000 copies/mL) without past or present serological evidence of having HBV or a response to hepatitis B vaccine. From December 2020 to February 2023, 561 adults were enrolled in the study at 41 sites in 10 countries in Africa, Asia, North America, and South America with follow-up for the primary outcome analysis through September 4, 2023., Interventions: Participants were randomly assigned to receive 2 doses of HepB-CpG vaccine administered intramuscularly at weeks 0 and 4; 3 doses of HepB-CpG vaccine administered intramuscularly at weeks 0, 4, and 24; or 3 doses of HepB-alum vaccine administered intramuscularly at weeks 0, 4, and 24., Main Outcomes and Measures: The primary outcome was a seroprotection response to hepatitis B vaccine (defined as level of antibody titer against hepatitis B surface antigen [HBsAg] ≥10 mIU/mL) at week 12 for the 2-dose regimen (8 weeks after dose 2) and at week 28 for 3-dose regimens (4 weeks after dose 3). Key secondary outcomes included seroprotection response at additional time points, antibody titer against HBsAg, and adverse events within 4 weeks of hepatitis B vaccination., Results: Of 561 participants included in the analysis (median age, 46 years [IQR, 31-56 years]); 64% were male; 17% of participants were Asian, 42% were Black, and 35% were White), a seroprotection response was achieved in 93.1% who received 2 doses of HepB-CpG vaccine (n = 174), in 99.4% who received 3 doses of HepB-CpG vaccine (n = 169), and in 80.6% who received 3 doses of HepB-alum vaccine (n = 165). The stratified difference in seroprotection response between the 2-dose HepB-CpG vaccine group and the 3-dose HepB-alum vaccine group was 12.5% (97.5% CI, 4.1%-20.9%), achieving noninferiority and indicating superiority. The 3-dose HepB-CpG vaccine regimen was superior to the 3-dose HepB-alum vaccine regimen (stratified difference in seroprotection response, 18.4% [repeated 97.5% CI, 10.4%-26.2%]). By week 12, more than 90% of participants who received HepB-CpG vaccine achieved a seroprotection response. The 3-dose regimen of HepB-CpG vaccine achieved a higher proportion of participants with antibody titer against HBsAg greater than 1000 mIU/mL (78.1%) vs the other 2 regimen groups (26.4% for 2 doses of HepB-CpG vaccine and 35.2% for 3 doses of HepB-alum vaccine). No unexpected safety issues were observed., Conclusions and Relevance: Among people with HIV and nonresponse to prior hepatitis B vaccination, both the 2-dose and 3-dose regimens of HepB-CpG vaccine achieved a superior seroprotection response compared with 3 doses of HepB-alum vaccine., Trial Registration: ClinicalTrials.gov Identifier: NCT04193189.

Introduction: Women with HIV (WHIV) have higher risks of adverse pregnancy outcomes, particularly in the absence of antiretroviral treatment(ART), and timing of ART may impact risk., Methods: In IMPAACT 2010 (VESTED), 643 pregnant WHIV in 9 countries were randomized 1:1:1 to initiate ART: dolutegravir (DTG)+emtricitabine(FTC)/tenofovir alafenamide(TAF); DTG+FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. We describe adverse pregnancy outcomes in women with a subsequent pregnancy during 50 weeks of postpartum follow-up: spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), preterm delivery (<37 weeks) and small-for-gestational-age (SGA)., Results: Of 643 women, 19 (3%) had 20 subsequent pregnancies while receiving ART at conception: DTG/FTC/TAF(3), DTG/FTC/TDF(2), EFV/FTC or lamivudine(3TC)/TDF(12), EFV/abacavir/3TC (1) and no ART(1). Four spontaneous abortions, 3 stillbirths, and 1 induced abortion occurred. Three (25%) of 12 liveborn infants were preterm (24-, 26- and 36-weeks' gestation). Only 12 (60%) subsequent pregnancies resulted in live birth, and at least 1 adverse pregnancy outcome occurred in 11/19 (58%) (induced abortion excluded). Of 7 women who experienced spontaneous abortion/stillbirth in the subsequent pregnancy, 4 experienced a stillbirth and 1 a neonatal death as outcomes of their earlier index pregnancy. No congenital anomalies were reported., Conclusions: Adverse pregnancy outcomes were common in this cohort of WHIV who conceived on ART shortly after an index pregnancy, 35% ended in stillbirth or spontaneous abortion. The majority of fetal losses occurred in women with recent prior pregnancy loss. Data from larger cohorts of WHIV conceiving on ART and surveillance are needed to elucidate rates and predictors of adverse pregnancy outcome. (249 words)., Competing Interests: Competing interests SB and LZ received NIH funding and ViiV Healthcare funding, both paid to their institution. RH serves on the editorial board for Elsevier’s Clinical Key, a clinical resource for clinicians.

Background: Isoniazid preventive therapy (IPT) is recommended for tuberculosis prevention yet data on the safety of first-trimester pregnancy exposure are limited., Methods: Planned secondary analysis in a TB prevention trial of adverse pregnancy outcomes among participants assigned to 9-month IPT who became pregnant during (IPT-exposed) or after (unexposed) IPT. Regression models compared binary outcomes of a composite adverse outcome (any non-live birth, excluding induced abortion); preterm delivery <37 weeks; and low birth weight <2500 g) among exposure groups. Models were adjusted for latent TB infection, maternal age, CD4 count, and antiretroviral therapy (ART)., Results: In total, 128 participants had a known pregnancy outcome; 39 IPT-exposed and 89 unexposed. At pregnancy outcome, ART use was lower in IPT-exposed (79%) than unexposed women (98%). Overall, 29 pregnancies ended in a composite adverse outcome (25 spontaneous abortions, 2 stillbirths and 2 ectopic pregnancies), 15 preterm deliveries, and 10 infants with low birth weight. IPT was associated with the composite adverse outcome adjusting for covariates at enrollment (adjusted relative risk [aRR] 1.98; 95% confidence interval [CI] 1.15, 3.41), but the effect was attenuated when adjusted for covariates at pregnancy outcome (aRR 1.47; 95% CI .84, 2.55); IPT was not associated with preterm delivery (relative risk [RR] 0.87; 95% CI .32-2.42) or low birth weight (RR 1.01; 95% CI .29, 3.56)., Conclusions: First-trimester IPT exposure was associated with nearly two-fold increased risk of fetal demise, mostly spontaneous abortion, though the association was attenuated when adjusted for covariates proximal to pregnancy outcome including ART use. Further study is needed to inform TB prevention guidelines., Competing Interests: Potential conflicts of interest. A. G. reports Advisory Board roles from NIAID and Indo-US Science and Technology Forum (IUSSTF). M. H. reports institutional research and training grants related to infectious diseases from US NIH; board membership of Botswana-Harvard Partnership through employer; spouse's research grants from NIH related to infectious diseases research. C. A. B. reports institutional grant support for clinical trials from Gilead and DNAe; consulting fees (paid to author) from National Data and Analytics Platform (NDAP), Inc.; honoraria for medical education lectures and travel support (paid to author) from International Antiviral Society–United States (IAS-USA), a non-profit medical education entity; and unpaid positions as Present of the non-profit Conference on Retroviruses and Opportunistic Infections (CROI) Foundation Board, and Secretary/Treasurer of the IAS-USA Board of Directors. R. E. C. reports spouse's stock in Merck. S. S. reports institutional research support from ViiV Healthcare and participation on a Data Safety Monitoring or Advisory board for now completed NIH coronavirus disease (COVID)-related trials. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Women are under-represented in clinical trials and must often commit to using contraception to enroll. We sought to determine the incidence and predictors of pregnancy in women participating in HIV treatment trials., Design: Individual participant data meta-analysis., Methods: We included data from multicountry HIV treatment trials conducted during the period 2005-2019 by the AIDS Clinical Trials Group that included females with HIV who were of reproductive potential, did not intend to become pregnant, and agreed to use effective contraception during study treatment. We extracted data from all female participants of age 18-55 years, including occurrence and dates of pregnancy on-study; however, only a few incident pregnancy predictor variables were available for analysis., Results: One thousand six hundred twenty-six women from 4 trials were included. Over a median of 28 months (6461 person-years) of follow-up, 143 (9%) women became pregnant, for an overall incidence of 2.2 pregnancies/100 person-years (range 0.5-3/100 person-years, by study). In multivariable analysis including baseline age, type of regimen, and country as predictor variables, younger age remained the strongest predictor of incident pregnancy ( P < 0.0001 adjusted for country and antiretroviral treatment regimen). CD4 and HIV-1 RNA were not associated with pregnancy incidence., Conclusions: Pregnancy incidence was 2.2/100 person-years in female participants of HIV treatment trials. Rather than leading to exclusion of young women from trials, this finding should prompt appropriate adaptations in study design and analysis for earlier generation of pregnancy safety information for drugs., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cytology-based cervical cancer screening followed by confirmation and treatment of biopsy-proven high-grade squamous intraepithelial lesions (bHSIL) is difficult to implement in resource-constrained settings. We hypothesized that high-risk human papillomavirus (hrHPV) testing followed by immediate cryotherapy of women with hrHPV (HPV screen-and-treat) may improve outcomes., Methods: Randomized, open-label, phase 2, multinational clinical trial enrolling women with human immunodeficiency virus (HIV) age 18 or older with cervical hrHPV and having no cervical lesions or lesions appropriate for cryotherapy. Women were randomized to immediate cryotherapy (Arm A) or cytology-based screening (Arm B). For Arm A, cervical biopsies were obtained followed by cervical cryotherapy, and in Arm B, women with abnormal cytology underwent colposcopy followed by loop electroexcision procedure (LEEP) if bHSIL was detected. Women were followed through 30 months. The primary outcome was time to bHSIL detected from Month 6 through study completion., Results: In total, 288 women (145 in Arm A, 143 in Arm B) were randomized: median age 35 years, 84% on antiretroviral therapy, median CD4 501 cells/mm3. In Arm A, 39 (27%) of women had bHSIL at entry, and in Arm B, 88 (62%) had abnormal cytology, 22 (15%) were diagnosed with bHSIL, 12 (8%) underwent LEEP. In follow-up, 30 (21%) and 31 (22%) developed bHSIL; time to bHSIL was similar between arms (P=.94). The prevalence of hrHPV at Month 6 was similar between arms (61% and 70%, P=.13)., Conclusions: HPV test-and-treat was not associated with improved bHSIL outcomes as compared to cytology-based screening. More effective treatment options are required to improve outcomes from screen-and-treat programs., Clinical Trials Registration: NCT01315363., Competing Interests: Potential conflicts of interest. T. J. W. has received grant funding paid to Weill Cornell Medicine from Bristol Myers-Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, and Merck Sciences, and has received honoraria from GlaxoSmithKline/ViiV Healthcare and Merck Sciences and reports consulting fees from Merck Sciences. H. C. reports support for attending meetings and/or travel from the NIH paid to the institution. S. G. reports support for the present manuscript from AIDS Clinical Trials Group, DAIDS NIH USA, for trial conduct. R. N. reports support for the present manuscript from AIDS Clinical Trials Group, funded by the Division of AIDS within the NIAID, payments made to the institution to support the ACTG Network’s Coordinating Center at Social & Scientific Systems, Inc. R. W. C. reports grants or contracts UM1 AI068636 and UM1 AI106701 outside of the submitted work. C. F. reports MERCK travel grant for airline tickets/hotel for CROI 2019 to present HPV/Cervical Dysplasia investigator driven study made to airline/hotel. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The Brief Rifapentine-Isoniazid Efficacy for TB Prevention/A5279 trial demonstrated a 1-month daily regimen of rifapentine and isoniazid was noninferior to 9 months of isoniazid alone for preventing TB in persons living with HIV (PLWH). Our objective was to evaluate rifapentine pharmacokinetics in trial participants receiving antiretroviral therapy (ART) and perform simulations to compare weight-based rifapentine dosing with a standard, fixed dose. Nonlinear mixed effect modeling was used to estimate rifapentine and 25-desacetyl rifapentine population pharmacokinetic characteristics. The pharmacokinetic model was validated using a nonparametric bootstrap and visual predictive checks. Monte Carlo simulations were performed to compare weight-based and fixed dose regimens. Rifapentine and 25-desacetyl rifapentine concentrations (347 of each; 185 participants) were each described with a one-compartment model with one-way conversion between rifapentine and 25-desacetyl rifapentine. The absorption rate was nearly doubled in fed versus fasting states. Rifapentine clearance was increased 31% in those receiving efavirenz (EFV)-based versus nevirapine-based ART. Metabolite clearance was allometrically scaled with fat-free mass. Simulations showed lower rifapentine exposures with weight-based compared with fixed dosing. With 10 mg/kg weight-based regimens, 26% and 62% of simulated exposures in <35 kg and 35-45 kg weight classes were above target (AUC 0 to 24 h of 257 mg*hr/L); 85% of simulated exposures across all weight classes with fixed dosing were above target. These data support fixed dosing with rifapentine 600 mg daily for TB prevention regardless of weight for PLWH 13 years or older receiving the 4-week regimen and no need for dose adjustment when given with EFV-based ART. Clinical Trials Registration. NCT01404312.

Objective: In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction., Methods: In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed., Results: Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing., Conclusions: Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation., Methods: This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration (<0.1 ng/mL) at week 12, was assessed using exact 95% Clopper-Pearson confidence intervals. MPA PK parameters were calculated using noncompartmental analysis., Results: Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/mm3. Five women (11.9%; 95% CI, 4.0-25.6%) had MPA <0.1 ng/mL at week 12; of these, one had MPA <0.1 ng/mL at week 10. The median clearance of MPA was 19 681 L/week compared with 12 118 L/week for historical controls. There were no adverse events related to DMPA, and progesterone concentrations were <1 ng/mL for all women for the study duration., Conclusions: DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed., Clinical Trials Registration: NCT02412436., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates., Methods: We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25., Results: A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001)., Conclusions: A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.)., (Copyright © 2019 Massachusetts Medical Society.)