Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Pharmacokinetics and safety of TBAJ-876, a novel antimycobacterial diarylquinoline, in healthy subjects.

TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin). TBAJ-876 was well-tolerated at single doses up to 800 mg and multiple doses up to 200 mg for 14 days. No deaths or serious adverse events occurred. No episodes of clinically significant prolongation of the QTc interval were observed. TBAJ-876 exposures were dose proportional in the SAD and MAD studies. TBAJ-876 exhibited multicompartmental pharmacokinetics (PK) with a long terminal half-life yielding quantifiable concentrations up to the longest follow-up of 10 weeks after a single dose and resulting in accumulation with multiple dosing. In the fed state, TBAJ-876 exposures approximately doubled with the tablet formulation, whereas M3 metabolite exposures decreased by approximately 20%. The relative bioavailability of TBAJ-876 was similar between tablets and the oral suspension at 100-mg doses. With co-administration of TBAJ-876, the AUC0-inf of midazolam was unchanged and the Cmax was reduced by 14%; the AUC0-last of digoxin was increased by 51%, and the Cmax was increased by 18%. These results support further investigation of TBAJ-876 for the treatment of tuberculosis.

Analysis of Dynamic Efficacy Endpoints of the Nix-TB Trial.

BACKGROUND: Safer, better, and shorter treatments for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are an urgent global health need. The phase 3 clinical trial Nix-TB (NCT02333799) tested a 6-month treatment of MDR and XDR-TB consisting of high-dose linezolid, bedaquiline, and pretomanid (BPaL). In this study, we investigate the relationship between the pharmacokinetic characteristics of the drugs, patient characteristics and efficacy endpoints from Nix-TB. METHODS: Pharmacokinetic data were collected at weeks 2, 8, and 16. Efficacy endpoints including treatment outcomes, time to stable culture conversion, and longitudinal time to positivity in the mycobacterial growth indicator tube assay were each characterized using nonlinear mixed-effects modeling. Relationships between patient, treatment pharmacokinetics, and disease characteristics and efficacy endpoints were evaluated. RESULTS: Data from 93 (85% of the total) participants were analyzed. Higher body mass index was associated with a lower incidence of unfavorable treatment outcomes. Median time to stable culture conversion was 3 months in patients with lower baseline burden compared with 4.5 months in patients with high baseline burden. Participants with minimal disease had steeper time to positivity trajectories compared with participants with high-risk phenotypes. No relationship between any drugs' pharmacokinetics (drug concentration or exposure metrics) and any efficacy outcomes was observed. CONCLUSIONS: We have successfully described efficacy endpoints of a BPaL regimen from the Nix-TB trial. Participants with high-risk phenotypes significantly delayed time to culture conversion and bacterial clearance. The lack of a relationship between pharmacokinetic exposures and pharmacodynamic biomarkers opens the possibility to use lower, safer doses, particularly for toxicity-prone linezolid. CLINICAL TRIALS REGISTRATION: NCT02333799.

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.

BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

Antibody Kinetics and Response to Routine Vaccinations in Infants Born to Women Who Received an Investigational Trivalent Group B Streptococcus Polysaccharide CRM197-Conjugate Vaccine During Pregnancy.

BACKGROUND: Maternal vaccination against group B Streptococcus (GBS) might provide protection against invasive GBS disease in infants. We investigated the kinetics of transplacentally transferred GBS serotype-specific capsular antibodies in the infants and their immune response to diphtheria toxoid and pneumococcal vaccination. METHODS: This phase 1b/2, observer-blind, single-center study (NCT01193920) enrolled infants born to women previously randomized (1:1:1:1) to receive either GBS vaccine at dosages of 0.5, 2.5, or 5.0 µg of each of 3 CRM197-glycoconjugates (serotypes Ia, Ib, and III), or placebo. Infants received routine immunization: combination diphtheria vaccine (diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine; age 6/10/ 14 weeks) and 13-valent pneumococcal CRM197-conjugate vaccine (PCV13; age 6/14 weeks and 9 months). Antibody levels were assessed at birth, day (D) 43, and D91 for GBS serotypes; 1 month postdose 3 (D127) for diphtheria; and 1 month postprimary (D127) and postbooster (D301) doses for pneumococcal serotypes. RESULTS: Of 317 infants enrolled, 295 completed the study. In infants of GBS vaccine recipients, GBS serotype-specific antibody geometric mean concentrations were significantly higher than in the placebo group at all timepoints and predictably decreased to 41%-61% and 26%-76% of birth levels by D43 and D91, respectively. Across all groups, ≥95% of infants were seroprotected against diphtheria at D127 and ≥91% of infants had seroprotective antibody levels against each PCV13 pneumococcal serotype at D301. CONCLUSIONS: Maternal vaccination with an investigational CRM197-glycoconjugate GBS vaccine elicited higher GBS serotype-specific antibody levels in infants until 90 days of age, compared with a placebo group, and did not affect infant immune responses to diphtheria toxoid and pneumococcal vaccination. CLINICAL TRIALS REGISTRATION: NCT01193920.

Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid.

Bedaquiline (B), pretomanid (Pa) and linezolid (L) are key components of new regimens for treating rifampicin-resistant tuberculosis (TB). However, there is limited information on the global prevalence of resistance to these drugs and the impact of resistance on treatment outcomes. Mycobacterium tuberculosis (MTB) phenotypic drug susceptibility and whole-genome sequence (WGS) data, as well as patient profiles from 4 pretomanid-containing trials-STAND, Nix-TB, ZeNix and SimpliciTB-were used to investigate the rates of baseline resistance (BR) and acquired resistance (AR) to BPaL drugs, as well as their genetic basis, risk factors and impact on treatment outcomes. Data from >1,000 TB patients enrolled from 2015 to 2020 in 12 countries was assessed. We identified 2 (0.3%) participants with linezolid BR. Pretomanid BR was also rare, with similar rates across TB drug resistance types (0-2.1%). In contrast, bedaquiline BR was more prevalent among participants with highly resistant TB or longer prior treatment histories than those with newly diagnosed disease (5.2-6.3% vs. 0-0.3%). Bedaquiline BR was a risk factor for bacteriological failure or relapse in Nix-TB/ZeNix; 3/12 (25%, 95% CI 5-57%) participants with vs. 6/185 (3.2%, 1.2-6.9%) without bedaquiline BR. Across trials, we observed no linezolid AR, and only 3 cases of bedaquiline AR, including 2 participants with poor adherence. Overall, pretomanid AR was also rare, except in ZeNix patients with bedaquiline BR. WGS analyses revealed novel mutations in canonical resistant genes and, in 7 MTB isolates, the genetic determinants could not be identified. The overall low rates of BR to linezolid and pretomanid, and to a lesser extent to bedaquiline, observed in the pretomanid trials are in support of the worldwide implementation of BPaL-based regimens. Similarly, the overall low AR rates observed suggest BPaL drugs are better protected in the regimens trialed here than in other regimens combining bedaquiline with more, but less effective drugs.

Sterile tuberculous granuloma in a patient with XDR-TB treated with bedaquiline, pretomanid and linezolid.

Drug-resistant tuberculosis (DR-TB) continues to pose a threat to the global eradication of TB. Regimens for extensively drug-resistant (XDR) TB are lengthy and poorly tolerated, often with unsuccessful outcomes. The TB Alliance Nix-TB trial investigated the safety and efficacy of a 26-week regimen of bedaquiline, pretomanid and linezolid (BPaL) in participants with XDR-TB, multidrug-resistant (MDR) TB treatment failure or intolerance. In this trial 9 out of 10 participants were cured. We describe a trial participant with XDR-TB who presented with new-onset seizures soon after BPaL treatment completion. Imaging showed a right temporal ring-enhancing lesion, and a sterile tuberculous granuloma was confirmed after a diagnostic, excisional biopsy. Learning points include management of a participant with a tuberculoma after BPaL completion, efficacy of new medications for central nervous system (CNS) TB and a review of their CNS penetration. This is the first case of pretomanid use in CNS TB.

Group B streptococcus vaccination in pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, multicentre trial.

BACKGROUND: Neonates born to women infected with HIV are at increased risk for invasive group B streptococcus (GBS) disease. We aimed to compare safety and immunogenicity of trivalent glycoconjugate GBS vaccine in pregnant women with and without HIV in Malawi and South Africa. METHODS: In our non-randomised phase 2, open-label, multicentre study, we recruited pregnant women attending two antenatal clinics, one in Blantyre, Malawi, and one in Soweto, Johannesburg, South Africa. Participants were divided into three groups on the basis of their HIV infection status (no infection, infection and high CD4 cell count [>350 cells per µL], and infection and low CD4 cell count [>50 to ≤350 cells per µL]) and received a 5 µg dose of glycoconjugate GBS vaccine (serotypes Ia, Ib, and III, with CRM197 [Novartis Vaccines, Siena, Italy]) intramuscularly at 24-35 weeks' gestation. GBS serotype-specific antibody concentrations were measured before vaccination (day 1), day 15, day 31, and at delivery, and in infants at birth and day 42 of life. The primary outcomes were safety in mothers and infants and the amount of placental transfer of GBS serotype-specific antibodies from mothers to their infants. All immunogenicity and safety analyses were done on the full analysis set, including participants who, or whose mother, correctly received the vaccine and who provided at least one valid assessable serum sample. This study is registered with ClinicalTrials.gov, number NCT01412801. FINDINGS: 270 women and 266 infants were enrolled between Sept 26, 2011, and Dec 4, 2012 (90 women and 87 infants without HIV, 89 and 88 with HIV and high CD4 cell counts, and 91 and 91 with HIV and low CD4 cell counts, respectively). Seven women were lost to follow-up, six withdrew consent, one died, and two relocated. Eight infants died or were stillborn and two were lost to follow-up. Across serotypes, fold change in antibody concentrations were higher for the HIV-uninfected group than the HIV-infected groups. Transfer ratios were similar across all three groups (0·49-0·72; transfer ratio is infant geometric mean antibody concentration in blood collected within 72 h of birth divided by maternal geometric mean antibody concentration in blood collected at delivery); however, at birth, maternally derived serotype-specific antibody concentrations were lower for infants born to women infected with HIV (0·52-1·62 µg/mL) than for those born to women not infected with HIV (2·67-3·91 µg/mL). 151 (57%) of 265 women reported at least one solicited adverse reaction: 39 (45%) of 87 women with HIV and low CD4 cell counts, 52 (59%) of 88 women with HIV and high CD4 cell counts, and 60 (67%) of 90 women in the HIV-uninfected group. 49 (18%) of 269 women had at least one adverse event deemed possibly related to the vaccine (six [7%] in the HIV and low CD4 cell count group, 12 [13%] in the HIV and high CD4 cell count group, and 21 [23%] in the HIV-uninfected group), as did three (1%) of 266 neonates (zero, two [1%], and one [1%]); none of these events was regarded as serious. INTERPRETATION: The vaccine was less immunogenic in women infected with HIV than it was in those not infected, irrespective of CD4 cell count, resulting in lower levels of serotype-specific maternal antibody transferred to infants, which could reduce vaccine protection against invasive GBS disease. A validated assay and correlate of protection is needed to understand the potential protective value of this vaccine. FUNDING: Novartis Vaccines and Diagnostics division (now part of the GlaxoSmithKline group of companies), Wellcome Trust UK, Medical Research Council: Respiratory and Meningeal Pathogens Research Unit.

Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in healthy women and their infants: a randomised phase 1b/2 trial.

BACKGROUND: Maternal group B streptococcus (GBS) serotype-specific capsular antibody concentrations are correlated with susceptibility to neonatal GBS invasive disease. Maternal immunisation against GBS during pregnancy might protect infants across the period of susceptibility to invasive disease, but no licensed vaccine exists. This study assessed the safety and immunogenicity of a CRM197-conjugated trivalent GBS vaccine in non-pregnant and pregnant women, and antibody transfer to their infants. METHODS: We did a phase 1b/2, randomised, observer-blind single-centre study of an investigational trivalent GBS vaccine in healthy non-pregnant women (cohort 1), and a dose-ranging study in healthy pregnant women (cohort 2). The study was done at the Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Participants were healthy non-pregnant or pregnant (28-35 weeks' gestation) women aged 18-40 years. In cohort 1, non-pregnant women were randomly assigned (2:1) to receive the investigational vaccine (two injections, 1 month apart, of a 20 µg dose [of each serotype] of aluminium hydroxide-adjuvanted investigational vaccine) or placebo. In cohort 2, pregnant women were randomly assigned (1:1:1:1) to receive one injection at 28-35 weeks' gestation of 0·5 µg, 2·5 µg, or 5·0 µg of the non-adjuvanted investigational vaccine (for each serotype), or placebo. All study participants and study staff not involved with vaccine preparation were masked to the randomisation group. The vaccine contained an equal dose (0·5 µg, 2·5 µg, 5·0 µg, or 20 µg) of each of three glycoconjugates (serotypes Ia, Ib and III). Reactogenicity was monitored to day 7 and unsolicited adverse events (adverse events) and infant safety were recorded throughout the study. The primary outcomes were tolerability and GBS-specific antibody response (measured as geometric mean concentrations [GMCs] in µg/mL) following the two injections for cohort 1, and selection of one vaccine dose based on analysis of serotype-specific antibody responses at delivery (+72 h) for use in subsequent studies. These outcomes were assessed in participants or infants of participants who correctly received the study vaccine with no major protocol deviations, and provided evaluable serum samples at day 1 and the scheduled timepoints throughout the study. This study is registered with ClinicalTrials.gov, NCT01193920. FINDINGS: Between Oct 5, 2010, and Sept 21, 2011, we screened 75 non-pregnant and 417 pregnant healthy South African women. Of these, 60 non-pregnant women were enrolled in cohort 1 (40 randomly assigned to the GBS 20 µg group and 40 randomly assigned to the placebo group) and 320 pregnant women were enrolled in cohort 2 (80 in each of the four groups). Among the randomised groups of pregnant women, 33-40% experienced at least one local and 54-71% one systemic solicited adverse event, less than 4% of which were severe, and the rate did not differ by study group. Also, 2% of the pregnancies resulted in stillbirth and 3·5% of the liveborn babies died by 12 months age, none of these deaths were attributed to vaccination. There was one death in a GBS-vaccine recipient, which too was unrelated to vaccination. For cohort 1, serotype-specific antibody concentrations were significantly higher, as evident by no overlap of the 95% CIs of GMCs against all three serotypes in the vaccinated group than the placebo group. For cohort 2, pregnant women in all vaccine groups had significantly higher GMCs than did those in the placebo group at delivery (eg, GMCs against serotype Ia were 11 µg/mL [95% CI 7·0-18] for the GBS vaccine 0·5 µg group, 18 µg/mL [11-29] for the GBS vaccine 2·5 µg group, 22 µg/mL [13-35] for the GBS vaccine 5·0 µg group, and 0·64 µg/mL [0·42-0·98] for the placebo group) and at all measured timepoints. GMCs did not differ significantly between the vaccine doses at any of the measured timepoints (p>0·05). INTERPRETATION: The vaccine was well tolerated and induced capsular-specific antibody responses, in non-pregnant and pregnant women. Maternal vaccination led to higher GBS serotype-specific antibody concentrations in infants than did placebo, with both interventions resulting in similar safety profiles. FUNDING: Novartis Vaccines and Diagnostics division, now part of the GlaxoSmithKline group of companies.

Lessons learnt from enrolment and follow up of pregnant women and their infants in clinical trials in South Africa, a low-middle income country.

INTRODUCTION: Infectious causes are a significant contributor to morbidity and mortality in neonates and young infants. Immunization of pregnant women to protect the mother and/or her infant is gaining momentum due to the benefits of this strategy demonstrated in numerous implemented strategies (Maternal and Neonatal Tetanus Elimination Initiative) and clinical trials. Reluctance by regulators, participants and healthcare providers to include pregnant women in clinical trials is considerable, but reducing. Infectious disease burden, and therefore need for interventions to reduce morbidity and mortality in mothers and infants, is highest in low-middle income countries (LMIC), however, reliable background data on adverse pregnancy outcomes and lack of experience in clinical trials and community opinions on immunization during pregnancy are not well documented. METHODS: We used our experiences in conducting two clinical studies in pregnant women in South Africa to illustrate the challenges experienced and lessons learnt which may benefit others working in the maternal immunization field. RESULTS: Accurate gestational age assessment, which is essential for clinical trials, is challenging in LMIC due to limited access to early ultrasound examinations, and unreliable assessment by history (last menstrual period date) and physical examination (symphyseal-fundal height). Concomitant administration of recommended vaccines has previously been avoided in clinical trials; however, this limitation could impact the potentially beneficial interventions that participants can access during antenatal care. Women in LMIC have a higher burden of concomitant illnesses (e.g. HIV infection, malaria and anaemia) and adverse pregnancy outcomes (e.g. stillbirth) than pregnant women in higher income countries. Availability of local data is essential for safety monitoring committees to identify vaccine-related adverse event triggers. CONCLUSION: Immunization of pregnant women to reduce disease burden in them and their infants is promising, and women in high-risk settings should be included in trials (Clinical trial registry number: 'Study A': NCT01193920, 'Study B': NCT01888471).