Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis.

Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log(10) decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log(10) CFU counts (+/- standard deviation) from baseline to day 7 were 0.04 +/- 0.46 for 25 mg TMC207 (n = 14), 0.26 +/- 0.64 for 100 mg TMC207 (n = 14), 0.77 +/- 0.58 for 400 mg TMC207 (n = 14), 1.88 +/- 0.74 for INH (n = 11), and 1.70 +/- 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.

A Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.

SETTING: Current treatment for pulmonary tuberculosis (TB) might be shortened by the incorporation of fluoroquinolones (FQs). OBJECTIVES: A Phase II study aimed to assess the sterilising activities of three novel regimens containing FQs before a Phase III trial of a 4-month regimen containing gatifloxacin (GFX). DESIGN: A total of 217 newly diagnosed smear-positive patients were randomly allocated to one of four regimens: isoniazid (INH), pyrazinamide and rifampicin (RMP) with either ethambutol, GFX, moxifloxacin (MFX) or ofloxacin (OFX) for 2 months. At the end of the study, RMP and INH were given for 4 months. The rates of elimination of Mycobacterium tuberculosis were compared in the regimens using non-linear mixed effects modelling of the serial sputum colony counts (SSCC) during the first 8 weeks. RESULTS: After adjustment for covariates, MFX substitution appeared superior during the early phase of a bi-exponential fall in colony counts, but significant and similar acceleration of bacillary elimination during the late phase occurred with both GFX and MFX (P = 0.002). Substitution of OFX had no effect. These findings were supported by estimates of time to conversion, using Cox regression, but there were no significant differences in proportions culture-negative at 8 weeks. CONCLUSIONS: GFX and MFX improve the sterilising activity of regimens and might shorten treatment; their progression into Phase III trials therefore seems warranted.

Resource utilization for multidrug-resistant tuberculosis household contact investigations (A5300/I2003).

BACKGROUND: Current guidelines recommend evaluation of the household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB); however, implementation of this policy is challenging. OBJECTIVE: To describe the resource utilization and operational challenges encountered when identifying and characterizing adult MDR-TB index cases and their HHCs. DESIGN: Cross-sectional study of adult MDR-TB index cases and HHCs at 16 clinical research sites in eight countries. Site-level resource utilization was assessed with surveys. RESULTS: Between October 2015 and April 2016, 308 index cases and 1018 HHCs were enrolled. Of 280 index cases with sputum collected, 94 were smear-positive (34%, 95%CI 28-39), and of 201 with chest X-rays, 87 had cavitary disease (43%, 95%CI 37-50) after a mean duration of treatment of 8 weeks. Staff required 512 attempts to evaluate the 308 households, with a median time per attempt of 4 h; 77% (95%CI 73-80) of HHCs were at increased risk for TB: 13% were aged <5 years, 8% were infected with the human immunodeficiency virus, and 79% were positive on the tuberculin skin test/interferon-gamma release assay. One hundred and twenty-one previously undiagnosed TB cases were identified. Issues identified by site staff included the complexity of personnel and participant transportation, infection control, personnel safety and management of stigma. CONCLUSION: HHC investigations can be high yield, but are labor-intensive.

Phase 1 trial of nonoxynol-9 film among sex workers in South Africa.

OBJECTIVES: To assess the acceptability and safety of a vaginal nonoxynol-9 film in a group of sex workers at a truck stop in South Africa. DESIGN: A randomized double-blinded crossover trial was conducted between April 1995 and July 1995. INTERVENTION: Seventy-two mg nonoxynol-9 film and an identical glycerine placebo film. METHODS: Following informed consent, each study participant was randomly assigned the designated pre-coded film for 1 month. The second month was a film-free washout period and the participants used the alternate film in the third month. Besides measuring behavioural and clinical outcomes, colposcopy examination for genital lesions, serology and microbiology investigations for sexually transmitted diseases and semi-quantitative PCR for vaginal HIV load estimates were performed. RESULTS: Twenty women participated in the study. The women reported, on average, 19 sexual encounters per week. Vaginal intercourse was protected 25% of the time by condoms. On average, 11 vaginal films, either nonoxynol-9 or placebos were inserted per week. There were no statistically significant differences between the two treatment groups for genital lesions (P = 0.29), reported side effects (P = 0.73), and viral load (P = 0.9). However, the proportions of clinically detected genital lesions (six out of eight versus two out of eight) and self-reported side-effects (five out of eight versus three out of eight) were higher in the nonoxynol-9 group when compared with the placebo group. Incident sexually transmitted diseases occurred more frequently in the placebo group. An increased viral load was associated with the development of a genital lesion (relative risk, 6.0; 95% confidence interval, 0.81-44.4). CONCLUSIONS: The 72 mg film formulation of nonoxynol-9 was an acceptable product for use in this population of sex workers. Although no statistically significant differences in adverse outcomes were detected, clinically there appeared to be an increase in minor lesions and self-reported side-effects with nonoxynol-9 and less protection against sexually transmitted diseases with the placebo. Furthermore, HIV shedding was correlated with the presence of incident vaginal or cervical lesions. This brings into question the potential narrow margin of safety for this product; additional Phase 2 studies are therefore required.

Microbicide research and development--where to?

PURPOSE: Against the backdrop of increasing numbers of HIV infections in women and the limitations of current safer sex messages, several calls have been made for the development of women-initiated methods of prevention as an essential component of the armamentarium to reduce women's vulnerability of acquiring infection with HIV. An effective microbicide is a critical survival tool in instances and situations where existing proven prevention strategies have failed to be adopted. METHOD: The results of published N-9 clinical trials in terms of anti-HIV activity, safety data, and anti-sexually transmitted infection (STI) activity are discussed. RESULTS: There is no evidence of efficacy against HIV in three clinical trials, there is scanty evidence for protection against STIs, and there is considerable evidence of dose-related adverse effects. CONCLUSION: During this time, a vast array of potential microbicides with differing modes of action have been discovered, and some have undergone preclinical and early clinical testing. Effort, time, and resources might be better spent on advancing preclinical and clinical testing of these other candidate microbicides.

Designing an adaptive phase II/III trial to evaluate efficacy, safety and immune correlates of new TB vaccines in young adults and adolescents.

This article summarises the consensus arrived at a meeting of South African and international stakeholders on specific late phase clinical trial design issues integrating the investigation of immune correlates as an integral part of a phase III protocol for a preventative TB vaccine in an adolescent/adult population. The challenge ahead is to optimize the planning for phase 3 TB vaccine preventative trials, under resource constraints, given that there are no known correlates of protection to shorten and increase the efficiencies of efficacy trials. An adaptive, multi-arm, group sequentially designed trial protocol is proposed incorporating design features that address uncertainties arising from both advances in the field and dynamic study populations and disease states. Such a design allows modifications that protect research subjects, save time, and maximize the impact of scarce financial resources. Further, the protocol underwent joint review by regulators from several African nations at a meeting of the African Vaccine Regulatory Forum (AVAREF), a regional regulatory harmonization initiative, and recommendations are included.

Key issues in the clinical development and implementation of TB vaccines in South Africa.

Significant progress has been made in advancing the development pipeline for a new and more effective TB vaccine with some candidate vaccines now in late stage clinical evaluation. However, progress has been hampered by an incomplete understanding of the components of a protective immune response and limited animal models, rendering the field unable to reliably predict vaccine efficacy earlier in preclinical development, including by evaluation in animal models, and limiting the predictive utility of comparing immunogenic effects across vaccine candidates in phase I/II studies. Consequently, new candidate vaccines have to be evaluated for efficacy in large-scale phase II/III trials using clinical endpoints. Apart from the technical challenges of characterising TB incidence in target populations at high risk of acquiring TB disease and standardising case definitions in order to improve both the sensitivity and more importantly the specificity of trial endpoints, there is an urgency in expanding and supporting the considerable trial infrastructure that will be required to evaluate and ultimately license a new TB vaccine. In the longer term, implementation strategies are dependent on what policy makers most value. Economic analyses will be essential to guide policy and implementation. This paper outlines the gaps and challenges and identifies solutions for effectively developing and efficiently introducing a new TB vaccine.