A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Development of a TB vaccine trial site in Africa and lessons from the Ebola experience.

Tuberculosis is the deadliest infection of our time. In contrast, about 11,000 people died of Ebola between 2014 and 2016. Despite this manifest difference in mortality, there is now a vaccine licensed in the United States and by the European Medicines Agency, with up to 100% efficacy against Ebola. The developments that led to the trialing of the Ebola vaccine were historic and unprecedented. The single licensed TB vaccine (BCG) has limited efficacy. There is a dire need for a more efficacious TB vaccine. To deploy such vaccines, trials are needed in sites that combine high disease incidence and research infrastructure. We describe our twelve-year experience building a TB vaccine trial site in contrast to the process in the recent Ebola outbreak. There are additional differences. Relative to the Ebola pipeline, TB vaccines have fewer trials and a paucity of government and industry led trials. While pathogens have varying levels of difficulty in the development of new vaccine candidates, there yet appears to be greater interest in funding and coordinating Ebola interventions. TB is a global threat that requires similar concerted effort for elimination.

A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

Chest Radiographs for Pediatric TB Diagnosis: Interrater Agreement and Utility.

The chest radiograph (CXR) is considered a key diagnostic tool for pediatric tuberculosis (TB) in clinical management and endpoint determination in TB vaccine trials. We set out to compare interrater agreement for TB diagnosis in western Kenya. A pediatric pulmonologist and radiologist (experts), a medical officer (M.O), and four clinical officers (C.Os) with basic training in pediatric CXR reading blindly assessed CXRs of infants who were TB suspects in a cohort study. C.Os had access to clinical findings for patient management. Weighted kappa scores summarized interrater agreement on lymphadenopathy and abnormalities consistent with TB. Sensitivity and specificity of raters were determined using microbiologically confirmed TB as the gold standard (n = 8). A total of 691 radiographs were reviewed. Agreement on abnormalities consistent with TB was poor; k = 0.14 (95% CI: 0.10-0.18) and on lymphadenopathy moderate k = 0.26 (95% CI: 0.18-0.36). M.O [75% (95% CI: 34.9%-96.8%)] and C.Os [63% (95% CI: 24.5%-91.5%)] had high sensitivity for culture confirmed TB. TB vaccine trials utilizing expert agreement on CXR as a nonmicrobiologically confirmed endpoint will have reduced specificity and will underestimate vaccine efficacy. C.Os detected many of the bacteriologically confirmed cases; however, this must be interpreted cautiously as they were unblinded to clinical features.

Placebo found equivalent to amoxicillin for treatment of acute bronchitis in Nairobi, Kenya: a triple blind, randomised, equivalence trial.

BACKGROUND: Antibiotic treatment is not recommended for acute bronchitis in immunocompetent patients in industrialised countries. Whether these recommendations are relevant to the developing world and to immunocompromised patients is unknown. DESIGN, SETTING AND PARTICIPANTS: Randomised, triple blind, placebo controlled equivalence trial of amoxicillin compared with placebo in 660 adults presenting to two outpatient clinics in Nairobi, Kenya, with acute bronchitis but without evidence of chronic lung disease. MAIN OUTCOME MEASURE: The primary study end point was clinical cure, as defined by a >or=75% reduction in a validated Acute Bronchitis Severity Score by 14 days; analysis was by intention to treat with equivalence defined as

Behaviour change in clients of health centre-based voluntary HIV counselling and testing services in Kenya.

OBJECTIVE: To explore behaviour change, baseline risk behaviour, perception of risk, HIV disclosure and life events in health centre-based voluntary counselling and testing (VCT) clients. DESIGN AND SETTING: Single-arm prospective cohort with before-after design at three (one urban and two rural) government health centres in Kenya; study duration 2 years, 1999-2001. SUBJECTS: Consecutive eligible adult clients. MAIN OUTCOME MEASURES: Numbers of sexual partners, partner type, condom use, reported symptoms of sexually transmitted infection, HIV disclosure and life events. RESULTS: High rates of enrollment and follow-up provided a demographically representative sample of 401 clients with mean time to follow-up of 7.5 months. Baseline indicators showed that clients were at higher risk than the general population, but reported a poor perception of risk. Clients with multiple partners showed a significant reduction of sexual partners at follow-up (16% to 6%; p<0.001), and numbers reporting symptoms of sexually transmitted infection decreased significantly also (from 40% to 15%; p<0.001). Condom use improved from a low baseline. Low rates of disclosure (55%) were reported by HIV-positive clients. Overall, no changes in rates of life events were seen. CONCLUSION: This study suggests that significant prevention gains can be recorded in clients receiving health centre-based VCT services in Africa. Prevention issues should be considered when refining counselling and testing policies for expanding treatment programmes.

Validation of a new clinical scoring system for acute bronchitis.

INTRODUCTION: Although several clinical prediction rules exist for lower respiratory tract infection (LRTI), few are for acute bronchitis (acute bronchitis) and most have not been validated in high human immunodeficiency virus (HIV) prevalence settings. METHODS: An Acute Bronchitis Severity Score (ABSS) was developed and validated during a randomized trial of antibiotic treatment for acute bronchitis. Ambulatory adults with productive cough of < or =2 weeks at out-patient respiratory disease clinics in Nairobi, Kenya, were recruited and assessed for clinical response to therapy. The ABSS quantitative ratings of LRTI-associated symptoms, physical signs and sputum Gram stain purulence were assessed using standard psychometric tests. RESULTS: The ABSS was evaluated among 649 cases of acute bronchitis; 129 (20%) were HIV-seropositive. The ABSS had small floor and ceiling effects (1.8/0.2) and demonstrated high internal consistency (alpha-coefficient of 0.66) and internal validity, with a mean inter item total correlation of > or =0.25. Effect sizes from baseline to subsequent follow-up visits were large (>0.5). Wheezing and chest pain were associated with higher ABSS values, whereas irrelevant clinical variables were not. CONCLUSION: The ABSS demonstrated good responsiveness, high internal consistency, good correlation with common respiratory signs and symptoms and high discriminatory validity among patients with acute bronchitis in a high HIV-seroprevalence setting.

Clinical presentation among HIV-infected and non-infected adults with community acquired pneumonia in Nairobi.

SETTING: Risk factors for mortality in hospitalized patients with community-acquired pneumonia (CAP) are well known. There are limited data on prognostic indicators among out-patients. OBJECTIVE: To compare the clinical presentation, outcome and prognostic factors for clinical improvement in human immunodeficiency virus (HIV) infected and non-HIV-infected out-patients with CAP. METHODOLOGY: Adults in Nairobi with CAP were treated with erythromycin as first-line therapy. Clinical symptoms were evaluated using a validated CAP-related symptom score (CSS). Clinical improvement was defined as reduction of baseline CSS by > or = 50%. RESULTS: Of 531 adults enrolled with CAP, 422 (79.5%) completed follow-up. Participants had a mean age (+/- SD) of 33.7 +/- 11.4 years, 274 (51.6%) were male and 193 (37%) were HIV-seropositive with a higher baseline CSS (27 vs. 25, P < 0.006). Overall, 196 of 422 (46%) had clinical improvement by 28 days. Factors independently associated with a longer time to clinical improvement included not being married (adjusted hazard ratio [aHR] 0.66, 95% CI 0.48-0.92) and higher baseline CSS (aHR 1.05, 95% CI 1.03-1.06). CONCLUSIONS: HIV-infected and non-infected patients with CAP responded similarly to out-patient treatment, but HIV-infected patients were more likely to present with severe symptoms. Baseline CSS and marital status were predictive of time to clinical improvement.

Trends in bloodstream infections among human immunodeficiency virus-infected adults admitted to a hospital in Nairobi, Kenya, during the last decade.

Bloodstream infections are a frequent complication in human immunodeficiency virus (HIV)-infected adults in Africa and usually associated with a poor prognosis. We evaluated bloodstream infections across a decade in 3 prospective cross-sectional surveys of consecutive medical admissions to the Kenyatta National Hospital, Nairobi, Kenya. Participants received standard clinical care throughout. In 1988-1989, 29.5% (28 of 95) of HIV-positive patients had bloodstream infections, compared with 31.9% (46 of 144) in 1992 and 21.3% (43 of 197) in 1997. Bacteremia and mycobacteremia were significantly associated with HIV infection. Infections with Mycobacterium tuberculosis, non-typhi species of Salmonella (NTS), and Streptococcus pneumoniae predominated. Fungemia exclusively due to Cryptococcus neoformans was uncommon. Clinical features at presentation remained similar. Significant improvements in the survival rate were recorded among patients with NTS bacteremia (20%-83%; P<.01) and mycobacteremia (0%-73%; P<.01). Standard clinical management can improve outcomes in resource-poor settings.