Johannesburg, South Africa
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Dawson R.,University of Cape Town | Diacon A.H.,Stellenbosch University | Everitt D.,Stellenbosch University | Van Niekerk C.,Global Alliance for TB Drug Development | And 18 more authors.
The Lancet | Year: 2015

Background New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment. Methods We did this phase 2b study of bactericidal activity - defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis - at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419. Findings Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0-56 (0·155, 95% Bayesian credibility interval 0·133-0·178) was significantly greater than for HRZE (n=54, 0·112, 0·093-0·131). DRMPa200Z (n=9) had bactericidal activity of 0·117 (0·070-0·174). The bactericidal activity on days 7-14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen. Interpretation The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment. Funding Global Alliance for TB Drug Development. © 2015 Elsevier Ltd.


Johnson L.F.,University of Cape Town | Mossong J.,University of KwaZulu - Natal | Dorrington R.E.,University of Cape Town | Schomaker M.,University of Cape Town | And 12 more authors.
PLoS Medicine | Year: 2013

Background:Few estimates exist of the life expectancy of HIV-positive adults receiving antiretroviral treatment (ART) in low- and middle-income countries. We aimed to estimate the life expectancy of patients starting ART in South Africa and compare it with that of HIV-negative adults.Methods and Findings:Data were collected from six South African ART cohorts. Analysis was restricted to 37,740 HIV-positive adults starting ART for the first time. Estimates of mortality were obtained by linking patient records to the national population register. Relative survival models were used to estimate the excess mortality attributable to HIV by age, for different baseline CD4 categories and different durations. Non-HIV mortality was estimated using a South African demographic model. The average life expectancy of men starting ART varied between 27.6 y (95% CI: 25.2-30.2) at age 20 y and 10.1 y (95% CI: 9.3-10.8) at age 60 y, while estimates for women at the same ages were substantially higher, at 36.8 y (95% CI: 34.0-39.7) and 14.4 y (95% CI: 13.3-15.3), respectively. The life expectancy of a 20-y-old woman was 43.1 y (95% CI: 40.1-46.0) if her baseline CD4 count was ≥200 cells/μl, compared to 29.5 y (95% CI: 26.2-33.0) if her baseline CD4 count was <50 cells/μl. Life expectancies of patients with baseline CD4 counts ≥200 cells/μl were between 70% and 86% of those in HIV-negative adults of the same age and sex, and life expectancies were increased by 15%-20% in patients who had survived 2 y after starting ART. However, the analysis was limited by a lack of mortality data at longer durations.Conclusions:South African HIV-positive adults can have a near-normal life expectancy, provided that they start ART before their CD4 count drops below 200 cells/μl. These findings demonstrate that the near-normal life expectancies of HIV-positive individuals receiving ART in high-income countries can apply to low- and middle-income countries as well.Please see later in the article for the Editors' Summary. © 2013 Johnson et al.


Marrazzo J.M.,University of Washington | Ramjee G.,HIV Prevention Research Unit | Richardson B.A.,Fred Hutchinson Cancer Research Center | Gomez K.,FHI 360 | And 23 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND: Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection. METHODS: We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly. RESULTS: Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 personyears. In the modified intention-to-treat analysis, the effectiveness was-49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29),-4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P = 0.004). We observed no significant differences in the frequencies of other adverse events. CONCLUSIONS: None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. Copyright © 2015 Massachusetts Medical Society.


Churchyard G.J.,Aurum Institute | Churchyard G.J.,University of Witwatersrand | Churchyard G.J.,London School of Hygiene and Tropical Medicine | Fielding K.L.,London School of Hygiene and Tropical Medicine | And 7 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Tuberculosis is epidemic among workers in South African gold mines. We evaluated an intervention to interrupt tuberculosis transmission by means of mass screening that was linked to treatment for active disease or latent infection. METHODS: In a cluster-randomized study, we designated 15 clusters with 78,744 miners as either intervention clusters (40,981 miners in 8 clusters) or control clusters (37,763 miners in 7 clusters). In the intervention clusters, all miners were offered tuberculosis screening. If active tuberculosis was diagnosed, they were referred for treatment; if not, they were offered 9 months of isoniazid preventive therapy. The primary outcome was the cluster-level incidence of tuberculosis during the 12 months after the intervention ended. Secondary outcomes included tuberculosis prevalence at study completion. RESULTS: In the intervention clusters, 27,126 miners (66.2%) underwent screening. Of these miners, 23,659 (87.2%) started taking isoniazid, and isoniazid was dispensed for 6 months or more to 35 to 79% of miners, depending on the cluster. The intervention did not reduce the incidence of tuberculosis, with rates of 3.02 per 100 person-years in the intervention clusters and 2.95 per 100 person-years in the control clusters (rate ratio in the intervention clusters, 1.00; 95% confidence interval [CI], 0.75 to 1.34; P = 0.98; adjusted rate ratio, 0.96; 95% CI, 0.76 to 1.21; P = 0.71), or the prevalence of tuberculosis (2.35% vs. 2.14%; adjusted prevalence ratio, 0.98; 95% CI, 0.65 to 1.48; P = 0.90). Analysis of the direct effect of isoniazid in 10,909 miners showed a reduced incidence of tuberculosis during treatment (1.10 cases per 100 person-years among miners receiving isoniazid vs. 2.91 cases per 100 person-years among controls; adjusted rate ratio, 0.42; 95% CI, 0.20 to 0.88; P = 0.03), but there was a subsequent rapid loss of protection. CONCLUSIONS: Mass screening and treatment for latent tuberculosis had no significant effect on tuberculosis control in South African gold mines, despite the successful use of isoniazid in preventing tuberculosis during treatment. (Funded by the Consortium to Respond Effectively to the AIDS TB Epidemic and others; Thibela TB Current Controlled Trials number, ISRCTN63327174.). Copyright © 2014 Massachusetts Medical Society.


Hawn T.R.,University of Washington | Day T.A.,Fred Hutchinson Cancer Research Center | Scriba T.J.,University of Cape Town | Hatherill M.,University of Cape Town | And 9 more authors.
Microbiology and Molecular Biology Reviews | Year: 2014

Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than infection, has been the primary target for vaccine development. Several areas of research highlight the importance of including preinfection vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of infection, with evidence that host responses may be more effective during acute infection than during chronic infection. Third, natural history studies indicate that resistance to TB infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from infection. Fifth, prevention-of-infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB vaccine development efforts to include prevention of infection as a primary goal along with vaccines or other interventions that reduce the rate of transmission and reactivation. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Van Halsema C.L.,London School of Hygiene and Tropical Medicine | Fielding K.L.,London School of Hygiene and Tropical Medicine | Chihota V.N.,Aurum Institute | Russell E.C.,London School of Hygiene and Tropical Medicine | And 3 more authors.
AIDS | Year: 2010

OBJECTIVE: Despite World Health Organization recommendations, concerns about promoting resistance have impeded implementation of isoniazid preventive therapy (IPT) for tuberculosis (TB). We describe characteristics of TB in individuals previously exposed to IPT as part of 'Thibela TB', a cluster-randomized trial of community-wide IPT in gold miners in South Africa. DESIGN: Case series including participants who were dispensed IPT, attended at least one follow-up visit and were subsequently treated for TB. METHODS: TB episodes were detected through surveillance and through follow-up if IPT was stopped early. Drug susceptibility data were compared with TB episodes detected through surveillance in control clusters (where IPT use was minimal) and a laboratory substudy of mycobacterial sputum culture from TB suspects in control clusters. RESULTS: Among 126 eligible individuals (125 men, median age 43 years), median time from starting IPT to TB treatment was 316 days (interquartile range 174-491). Ninety-four of the 126 (75%) were first episodes. Eighty-nine of 103 (86%) tested HIV-infected, with the median CD4 cell count of 196 cells/μl (n = 51). Sixty-four of 108 (59%) with known treatment outcomes were cured or completed treatment. Among 71 isolates with drug susceptibility results available, 12.1% [95% confidence interval (CI) 5.0-23.3] and 7.7% (95% CI 0.2-36.0) from first and retreatment episodes, respectively, had isoniazid resistance, compared with 6.0% (95% CI 3.1-10.2) and 18.7% (95% CI 10.6-29.3) in control clusters and 11.8% (95% CI 8.2-16.3) among first TB episodes in the laboratory substudy. CONCLUSION: TB after recent IPT has prevalence of drug resistance similar to background and treatment outcomes typical of this setting. These data support wider implementation of IPT. Copyright © 2010 Lippincott Williams & Wilkins.


Lester R.,London School of Hygiene and Tropical Medicine | Hamilton R.,Aurum Institute | Charalambous S.,Aurum Institute | Dwadwa T.,Aurum Institute | And 3 more authors.
AIDS | Year: 2010

Objectives: Despite good evidence that isoniazid preventive therapy (IPT) reduces incidence of tuberculosis among people with HIV infection, implementation of IPT is low. This study aimed to describe barriers to IPT implementation from healthcare provider and patient perspectives in a donor-funded HIV care programme in Gauteng province, South Africa, in which IPT is recommended, but delivery is variable. Design: A qualitative study using in-depth interviews and a focus group discussion. Methods: We conducted interviews with 22 clinic staff and 20 patients from 10 purposively selected HIV clinics, and a staff focus group discussion. Staff were questioned on their knowledge and experience of IPT, and asked about barriers to its use. Patients were asked for their opinions about taking IPT. Results: Healthcare workers reported the primary barrier to IPT use was lack of knowledge and experience. Prescribers were unaware of the benefits of IPT and unclear about guidelines. The belief that existing screening tools are inaccurate in HIV-infected individuals and the need to refer patients to separate clinics for tuberculosis screening also emerged as barriers. No patients had heard of IPT. Conclusion: Barriers to the widespread use of IPT primarily derived from healthcare workers, in particular, lack of experience among physicians. In addition to overcoming operational barriers, a change in healthcare worker perception is needed if IPT is to be widely used; we suggest local clinical opinion leaders could help achieve this. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Thind D.,London School of Hygiene and Tropical Medicine | Charalambous S.,Aurum Institute | Tongman A.,Aurum Institute | Churchyard G.,Aurum Institute | Grant A.D.,London School of Hygiene and Tropical Medicine
International Journal of Tuberculosis and Lung Disease | Year: 2012

SETTING: Rural/peri-urban community, South Africa. OBJECTIVES: To examine the yield of tuberculosis (TB) cases, TB preventive therapy (TBPT) initiation and human immunodeficiency virus (HIV) diagnoses from household TB contact tracing. DESIGN: Retrospective programme analysis. METHODS: Households of index TB cases were visited and their contacts screened for TB and HIV. TB suspects provided sputum or were referred for assessment. Contacts aged <5 years were referred for assessment for TBPT initiation. RESULTS: There were 732 index TB cases (67.1% HIVpositive). Among 3627 household contacts, 3573 (98.5%) had known outcomes, of which 183 (5.0%) were already on appropriate treatment. Among 3390 remaining contacts, 361 (10.6%) were aged <5 years, of whom 34 (9.4%) started anti-tuberculosis treatment and 286 (79.2%) started TBPT. Among 3029 contacts aged ≥5 years, 93 (3.1%) started anti-tuberculosis treatment: 19 (20.4%) were smear-positive and 71 (76.3%) were culture-positive. Among contacts aged ≥14 years, 794/2133 (37.2%) underwent HIV testing, of whom 208/794 (26.2%) tested positive. CONCLUSIONS: Household active case finding in this high TB and HIV prevalence setting obtained high yields of TB, particularly in those aged <5 years, and facilitated assessment for TBPT. There was a good yield of new HIV diagnoses, and a gain in efficiency due to integration within one programme. © 2012 The Union.


Wallis R.S.,Aurum Institute | Peppard T.,St Louis
Clinical Infectious Diseases | Year: 2015

Biomarkers play an essential role in accelerating drug development. Sputum culture conversion using solid medium is the best-characterized tuberculosis biomarker, having been examined at the patient and trial levels in studies with thousands of subjects, and having recently been validated using data from 3 unsuccessful phase 3 trials. We presently are poised at the threshold of regulatory innovation for antibacterials to treat drug-resistant infections, in which Special Medical Use authorization restricted to patients with limited options could be based on the results of small clinical trials. Patients worldwide would be well served by licensing of new regimens for multidrug-resistant tuberculosis based on biomarker evidence commensurate with the urgency of the current global crisis. © 2015 The Author.


Wallis R.S.,Aurum Institute | Hafner R.,U.S. National Institutes of Health
Nature Reviews Immunology | Year: 2015

Improved treatments are needed for nearly all forms of Mycobacterium tuberculosis infection. Adjunctive host-directed therapies have the potential to shorten tuberculosis treatment duration, prevent resistance and reduce lung injury by promoting autophagy, antimicrobial peptide production and other macrophage effector mechanisms, as well as by modifying specific mechanisms that cause lung inflammation and matrix destruction. The range of candidates is broad, including several agents approved for other clinical indications that are ready for evaluation in Phase II clinical trials. The promise of new and existing host-directed therapies that could accelerate response and improve tuberculosis treatment outcomes is discussed in this Opinion article. © 2015 Macmillan Publishers Limited. All rights reserved.

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